Estrogen receptor protein degradation-targeting chimera compound and use thereof

Abstract

Provided in the present invention are a new compound binding to an estrogen receptor protein, an estrogen receptor protein degradation-targeting chimera compound, and the medical use thereof. The compound provided in the present invention can be used as an estrogen receptor degrader for treating estrogen-dependent diseases.

Description

A chimeric compound targeting estrogen receptor protein degradation and its application

[0001] This application requires the following filings: application number CN2024107944455 filed on June 19, 2024; application number CN2024108679368 filed on July 1, 2024; application number CN2024110529551 filed on August 2, 2024; application number CN2024111252283 filed on August 16, 2024; application number CN2024113897930 filed on October 8, 2024; application number CN2024115386041 filed on October 31, 2024; application number CN2024119493254 filed on December 27, 2024; and application number CN202510302 filed on March 14, 2025. The priority of Chinese patent applications filed on April 26, 2025 (application number CN2025105334168), June 3, 2025 (application number CN2025107260686), August 2, 2024 (application number CN2024110572316), August 15, 2024 (application number CN2024111197892), December 27, 2024 (application number CN2024119467368), March 24, 2025 (application number CN2025103480526), ​​and April 26, 2025 (application number CN2025105334153) is hereby granted, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure relates to the field of pharmaceutical technology, specifically to a compound used as an estrogen receptor degrader and its uses. Background Technology

[0003] The concept of PROTACs (Proteolysis Targeting Chimeras) technology was proposed in 2001 (Proc. Natl. Acad. Sci. USA, 2001, 98, 8584). Early PROTACs recruited E3 ligases via peptides, but their poor membrane permeability limited their activity. Small-molecule PROTACs based on MDM2E3 ligases emerged in 2008, but their activity was still limited. It wasn't until 2010-2012 that commonly used ligands based on cerebellar proteins (CRBN, cereblon) and von Hippel-Lindau (VHL) E3 ligases were developed, enabling micromolar binding levels between small ligands and E3 ligases, laying the foundation for the development of subsequent PROTACs. PROTACs are bifunctional molecules, containing a ligand binding to E3 ubiquitin ligase at one end and a ligand binding to the target protein at the other, linked by a linker unit. By bringing the E3 ligase and target protein very close through the linker unit, PROTACs induce polyubiquitination and proteasome degradation of the target protein. PROTACs employ a completely different mechanism of action than small molecule inhibitors. First, the ligand of the E3 ubiquitin ligase recruits it to the vicinity of the target protein, thereby ubiquitinizing it. The labeled target protein is then degraded by the proteasome system in vivo, thus inhibiting the corresponding protein pathway (Cell Biochem Funct. 2019, 37, 21-30). Compared to traditional small molecule drugs, due to the altered binding mechanism, PROTACs only require transient binding to the target protein to complete the ubiquitin transfer process and achieve irreversible degradation. Therefore, PROTACs have the following advantages: 1) stronger degradation and longer-lasting efficacy; 2) higher selectivity for the target protein; 3) overcoming drug resistance caused by target protein mutations in traditional small molecule inhibitors (Cell Chem. Biol. 2018, 25, 67-77).

[0004] The estrogen receptor (ER) is a member of the nuclear hormone receptor family and acts as a ligand-activated transcription factor involved in the upregulation and downregulation of gene expression. The natural hormone of the estrogen receptor is estradiol (E2) and its closely associated metabolites. The binding of estradiol to the estrogen receptor causes receptor dimerization, which in turn binds to estrogen response elements (EREs) on DNA. The ER-DNA complex recruits other transcription factors responsible for transcribing downstream DNA into mRNA, which is ultimately converted into protein. Alternatively, the interaction between ER and DNA can occur indirectly through the intermediaries of other transcription factors, most notably fos and jun. Because the expression of a large number of genes is regulated by the estrogen receptor, and because the estrogen receptor is expressed in many cell types, estrogen receptor regulation, through binding to natural hormones or synthetic ER ligands, can have profound physiological and pathophysiological effects on organisms.

[0005] Several protac compounds targeting the ER already exist clinically, such as ARV-471, developed by Arvinas for the treatment of women with locally advanced or metastatic estrogen receptor (ER)-positive / human epidermal growth factor receptor 2 (HER2)-negative (ER+ / HER2-) breast cancer. Its molecular weight is 723.92, and its calculated log P-value is approximately 4-6. However, studies have found it to be poorly soluble in aqueous solutions and it has been reported to be taken with food in clinical studies. Poor water solubility and low oral absorption are bottlenecks in the development of RPTAC molecules for in vivo application. Therefore, novel estrogen receptor degrading agents are needed clinically. Summary of the Invention

[0006] This disclosure provides a novel estrogen receptor protein degradation-targeting chimeric PROTAC compound molecule. These molecules exhibit significant activity as estrogen receptor degraders in the treatment of estrogen receptor-mediated or dependent diseases.

[0007] This disclosure provides a compound represented by formula (II):

[0008] CLM―L―PTM(Ⅱ),

[0009] Or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates,

[0010] in:

[0011] CLM is the ubiquitin-binding site of the cerebellar protein E3;

[0012] L is the bond that covalently connects the CLM and PTM, or -(B L ) q -;

[0013] PTM is the binding site that targets the estrogen receptor protein, and it comprises the structure shown in formula (III):

[0014] In the formula, R1 and R2 are each independently selected from N or CR. mm ;

[0015] R3 is selected from H, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally substituted by 1, 2, 3, 4, or 5 substituents each independently selected from carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl;

[0016] R4 is selected from N or CR m4 ;

[0017] R5 is selected from N or CR m5 ;

[0018] R6 is selected from N or CR m6 ;

[0019] R7 is selected from N or CR m7 ;

[0020] R mm R m8 R m9 R m10 and R m11 Each time it appears, it is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl; or

[0021] R m4 and R m5Each time it appears, it is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl; or R m4 and R m5 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloyl group, C6-C 10 The aryl group is substituted with one or more substituents of a 5-10 member heteroaryl group; or R4 is CR. m4 When R5 is N, R m4 R5 and R m4 The attached carbon atoms form 4-10 membered heterocyclic alkyl groups containing 1-3 heteroatoms, each independently selected from N, O, and S;

[0022] R m6 and R m7 Each time it appears, it is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl; or R m6 and R m7 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, C6-C 10 Aryl, C5-C 10Substituted by one or more substituents of heteroaryl and 5-10 heteroaryl groups; or

[0023] In the PTM, when R1 and R2 are both CH, R m9 When H is present, (a)R m4 and R m5 And the atoms they are connected to form saturated or unsaturated ring structures, or (b)R m6 and R m7 The carbon atoms to which they are attached form a saturated or unsaturated ring structure, or (c) one of R4 and R6 is selected from N; preferably, at least one of R4 and R6 is selected from N; or R mm R m8 and R m9 At least one of them is not H in each occurrence;

[0024] B L Each occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, SO, SO2, NR L3 SO2NR L3 SONR L3 C(O)NR L3 NR L3 C(O)NR L4 NR L3 SO2NR L4 C(O), CR L1 =CR L2 C≡C, SiR L1 R L2 P(O)R L1 P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 0-6 R groups. L1 and / or R L2 Group substitution;

[0025] R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, C. 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, C(O)-C 3-8 Cycloalkyl, C(O)-C 3-11 Heterocyclic, O-aryl, O-heteroaryl, SC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, N(C) 3-8 cycloalkyl)2, N(C) 3-8 cycloalkyl)(C 1-8 Alkyl), N(C) 1-8 Alkylene)(C 3-8 cycloalkyl), NH-C 3-8 Heterocyclic groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8 Heterocyclic group)(C 1-8 Alkyl), NH-aryl, N(aryl) (C 1-8 Alkyl), NH-heteroaryl, N(heteroaryl) (C 1-8 Alkyl), OH, NH2, SH, SO2P(O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, C(O)-C 1-8 Alkyl, C(O)OC 1-8 Alkyl, C(O)2H, CN, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C) 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C) 1-8 Alkyl)2、C(O)NH-C 1-8 Alkyl, C(O)NH-C 3-8 cycloalkyl, C(O)NH-C 3-11 Heterocyclic groups, C(O)N(C) 1-8 Alkyl)2, N(C) 1-8alkyl)C(O)NH(C 1-8 Alkyl), N(C) 1-8 alkyl)C(O)N(C 1-8 Alkyl)2、NHC(O)NH(C 1-8 Alkyl), NHC(O)N(C 1-8 Alkyl)2, NHC(O)NH2, N(C) 1-8 alkyl)SO2NH(C 1-8 Alkyl), N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 Alkyl), NH SO2N (C 1-8 Alkyl)2 and NH SO2NH2, optionally, wherein the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic group, C 6-10 The aryl and 5-10 heteroaryl groups are each independently substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxyl, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloyl, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl and haloheteroaryl;

[0026] q is an integer greater than or equal to 1;

[0027] In some implementations, the CLM is the cerebellar protein E3 ubiquitin ligase binding moiety;

[0028] L is the bond that covalently connects the CLM and PTM, or -(B L ) q -;

[0029] PTM is the binding site that targets the estrogen receptor protein, and it comprises the structure shown in formula (III):

[0030] In the formula, R1 and R2 are each independently selected from N or CR. mm ;

[0031] R3 is selected from H, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally substituted by 1, 2, 3, 4, or 5 substituents each independently selected from carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl;

[0032] R4 is selected from N or CR m4 ;

[0033] R5 is selected from N or CR m5 ;

[0034] R6 is selected from N or CR m6 ;

[0035] R7 is selected from N or CR m7 ;

[0036] R mm R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each time it appears, it is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl; or

[0037] R m4 and R m5The carbon atom to which it is attached is capable of forming a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloyl group, C6-C 10 The aryl group is substituted with one or more substituents of 5-10 heteroaryl groups; or

[0038] R m6 and R m7 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, C6-C 10 Aryl, C5-C 10 Substituted by one or more substituents of heteroaryl and 5-10 heteroaryl groups; or

[0039] R4 is CR m4 When R5 is N, R m4 R5 and R m4 The attached carbon atoms can form 4-10 membered heterocyclic alkyl groups containing 1-3 heteroatoms, each independently selected from N, O, and S;

[0040] In the PTM, when R1 and R2 are both CH, R m9 When H is present, (a)R m4 and R m5 And the atoms they are connected to form saturated or unsaturated ring structures, or (b)R m6 and R m7 The carbon atoms to which they are attached form saturated or unsaturated ring structures, or (c) one of R4 and R6 is selected from N; or R mm R m8 and R m9 At least one of them is not H in each occurrence;

[0041] B L Each occurrence may be the same or different, and each is independently selected from: CR L1 RL2 O, S, SO, SO2, NR L3 SO2NR L3 SONR L3 C(O)NR L3 NR L3 C(O)NR L4 NR L3 SO2NR L4 C(O), CR L1 =CR L2 C≡C, SiR L1 R L2 P(O)R L1 P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 0-6 R groups. L1 and / or R L2 Group substitution;

[0042] R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, C. 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, C(O)-C 3-8 Cycloalkyl, C(O)-C 3-11 Heterocyclic, O-aryl, O-heteroaryl, SC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, N(C) 3-8 cycloalkyl)2, N(C) 3-8 cycloalkyl)(C 1-8 Alkyl), N(C) 1-8 Alkylene)(C 3-8 cycloalkyl), NH-C 3-8 Heterocyclic groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8Heterocyclic group)(C 1-8 Alkyl), NH-aryl, N(aryl) (C 1-8 Alkyl), NH-heteroaryl, N(heteroaryl) (C 1-8 Alkyl), OH, NH2, SH, SO2P(O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, C(O)-C 1-8 Alkyl, C(O)OC 1-8 Alkyl, C(O)2H, CN, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C) 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C) 1-8 Alkyl)2、C(O)NH-C 1-8 Alkyl, C(O)NH-C 3-8 cycloalkyl, C(O)NH-C 3-11 Heterocyclic groups, C(O)N(C) 1-8 Alkyl)2, N(C) 1-8 alkyl)C(O)NH(C 1-8 Alkyl), N(C) 1-8 alkyl)C(O)N(C 1-8 Alkyl)2、NHC(O)NH(C 1-8 Alkyl), NHC(O)N(C 1-8 Alkyl)2, NHC(O)NH2, N(C) 1-8 alkyl)SO2NH(C 1-8 Alkyl), N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 Alkyl), NH SO2N (C 1-8 Alkyl)2 and NH SO2NH2, optionally, wherein the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic group, C6-10 The aryl and 5-10 heteroaryl groups are each independently substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxyl, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl and haloheteroaryl.

[0043] In some implementations, the CLM includes a structure selected from the following:

[0044] Among them, W 1 and W 2 Each independently for CR a R b C (=O), NR a Or SO2, and W 1 and W 2 At least one of them is C (=O);

[0045] G and Z are each independently selected from O, S, and Se;

[0046] W 5 W 6 Each occurrence is independently C(R) m 2. NR m , O or S;

[0047] W 11 For CR a R b C (=O), NR a Or SO2;

[0048] R8, R9, R a R m R N and R b Each time it appears, it is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl and C1-C6 alkylNHacyl;

[0049] R 22 Selected from single bonds, C(O), O, S, SO2, -NR m -、-NR m Combinations of one or more of C(O)-, alkylene, alkenylene, ynylene, haloalkylene, and heteroalkylene;

[0050] n is 0, 1, 2, or 3;

[0051] R 32 and R 42 Together with the carbon atoms attached to it, it forms And R 52 R 62 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C2-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups; or

[0052] R 42 and R 52 Together with the carbon atoms attached to it, it forms And R 32 R 62 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C2-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups; or

[0053] R52 and R 62 Together with the carbon atoms attached to it, it forms And R 32 R 42 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C2-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups;

[0054] R d R e R f R g R D R E R F R G R f1 R g1 R F1 and R G1 Each occurrence is independently C(R) m 2. NR m O, C(O) or S;

[0055] W 3 and W 4 Each independently for CR m Or N;

[0056] R t R T R t1 R T1 Each independently for CR m Or N, R t R T R t1 R T1 Side connection Represents the connection site between CLM and L;

[0057] Each occurrence of m1 and m2 is independently 0, 1, 2, 3, 4, 5 or 6, and m1 + m2 ≤ 6;

[0058] m3 appears each time as 0, 1, 2, 3, 4, 5, 6 or 7, m4 appears each time as 1, 2, 3, 4, 5, 6, 7 or 8, and m3 + m4 ≤ 8;

[0059] Each occurrence of m5 and m6 is independently 0, 1, 2, 3, 4, 5, 6 or 7, and m5 + m6 ≤ 7;

[0060] Each occurrence of m7 and m8 is independently 0, 1, 2, 3, 4, 5, 6 or 7, and m7 + m8 ≤ 7;

[0061] m31 is an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m41 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8, and m31 + m41 ≤ 8; and

[0062] m51 is an integer of 0, 1, 2, 3, 4, 5, 6 or 7, m61 is an integer of 1, 2, 3, 4, 5, 6, 7 or 8, and m51 + m61 ≤ 8.

[0063] In some implementations, R1 is CR mm ; and / or

[0064] R2 is CR mm ; and / or

[0065] R3 is R m1 R m2 and R m3 Each time it appears, it is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl; in some embodiments, R m1 R m2 and R m3 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; in some embodiments, R m1 R m2 and R m3 Each occurrence is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups; in some embodiments, Rm1 R m2 and R m3 Each occurrence is independently of H, C1-C3 alkyl, F, Cl, Br, or I; and / or

[0066] R mm R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino, and R mm R m8 and R m9 Each occurrence must contain at least one non-H; in some implementations, R mm R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino, and R mm and R m9 Each occurrence must contain at least one non-H; in some implementations, R mm R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, and R mm R m8 and R m9 Each occurrence must have at least one element that is not H; furthermore, in some implementations, R mm R m4 R m5 R m6 R m7 R m8 R m9 Rm10 and R m11 Each occurrence is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, and R mm R m8 and R m9 Each occurrence must have at least one element that is not H; in some implementations, R mm R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, and R1 is not CH; in some embodiments, R mm R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently of H, C1-C3 alkyl, F, Cl, Br, and I, and R mm R m8 and R m9 Each occurrence must have at least one element that is not H; in some implementations, R mm R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently of H, C1-C3 alkyl, F, Cl, Br, and I, and R1 is not CH; in some embodiments, R mm R m8 and R m9 Each occurrence is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, and at least one is not H; in some embodiments, R mm R m8 and R m9 Each occurrence is independently of H, C1-C3 alkyl, F, Cl, Br, and I, and R mm and R m9 Each occurrence must have at least one element that is not H; in some implementations, R mm R m8 and R m9Each occurrence is independently of H, C1-C3 alkyl, F, Cl, Br, and I, and R mm Each occurrence must have at least one element that is not H; in some implementations, R mm R m8 and R m9 Each occurrence is independently of H, C1-C3 alkyl, F, Cl, Br, and I, and R1 is not CH; or

[0067] R m4 and R m5 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 5-7 membered cycloalkyl group or a 5-7 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the saturated or unsaturated 5-7 membered cycloalkyl group or the 5-7 membered heterocycloalkyl group is unsubstituted or substituted by one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, nitro, cyano, and amino; or

[0068] R m6 and R m7 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 5-7 membered cycloalkyl group or a 5-7 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the saturated or unsaturated 5-7 membered cycloalkyl group or the 5-7 membered heterocycloalkyl group is unsubstituted or substituted by one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, nitro, cyano, and amino; or

[0069] R4 is CR m4 When R5 is N, R m4 R5 and R m4 The attached carbon atom can form a 5-7 membered heterocyclic alkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S; and / or

[0070] R mm and R m9 Each occurrence must contain at least one non-H; in some implementations, R mm At least one of them is not H each time it occurs; and in some implementations, R1 is not CH; and / or

[0071] B L Each occurrence is independently selected from: CR L1 R L2 O, S, SO, SO2, NR L3CO, C≡C, 3-16 cycloalkylene, 3-16 heterocyclic, 6-10 aryl, and 5-10 heteroaryl, wherein the 3-16 cycloalkylene, 3-16 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are optionally surrounded by 0, 1, 2, or 3 Rs. L1 and / or R L2 Group substitution; and / or

[0072] R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, C. 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, C(O)-C 3-8 Cycloalkyl, C(O)-C 3-11 Heterocyclic, O-aryl, O-heteroaryl, SC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, N(C) 3-8 cycloalkyl)2, N(C) 3-8 cycloalkyl)(C 1-8 Alkyl), N(C) 1-8 Alkylene)(C 3-8 cycloalkyl), NH-C 3-8 Heterocyclic groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8 Heterocyclic group)(C 1-8 Alkyl), NH-aryl, N(aryl) (C 1-8 Alkyl), NH-heteroaryl, N(heteroaryl) (C 1-8 Alkyl), OH, NH2, SH, SO2P(O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, C(O)-C 1-8 Alkyl, C(O)OC 1-8 Alkyl, C(O)2H, CN, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C) 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C) 1-8 Alkyl)2、C(O)NH-C 1-8 Alkyl, C(O)NH-C 3-8 cycloalkyl, C(O)NH-C 3-11 Heterocyclic groups, C(O)N(C) 1-8 Alkyl)2, N(C) 1-8 alkyl)C(O)NH(C 1-8 Alkyl), N(C) 1-8 alkyl)C(O)N(C 1-8 Alkyl)2、NHC(O)NH(C 1-8 Alkyl), NHC(O)N(C 1-8 Alkyl)2, NHC(O)NH2, N(C) 1-8 alkyl)SO2NH(C 1-8 Alkyl), N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 Alkyl), NH SO2N (C 1-8 Alkyl)2 and NH SO2NH2, wherein the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and selectively chosen from F, Cl, Br, I, C. 1-6 Substituted by one or more substituents selected from alkyl, methoxy, and ethoxy groups; and / or

[0073] q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and / or

[0074] W 1 W 2 Each occurrence is independently designated as CR. a R b Or C (=O); in some implementations, W 1 For C (=O), W 2 For CH or W1 For CH, W 2 For C (=O); and / or

[0075] G is O; Z is O; and / or

[0076] W 5 W 6 Each occurrence is independently C(R) m )2; In some implementation schemes, W 5 CH2, W 6 CH2; and / or

[0077] W 11 For C (=O); and / or

[0078] R8, R9, R a R m R N and R b Each of the following is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; in some embodiments, R8 and R9 are each independently H or C1-C3 alkyl, preferably H or methyl, more preferably H; in some embodiments, R N It is H or C1-C3 alkyl, preferably H or methyl, more preferably methyl; and / or

[0079] R 22 Selected from single bonds, C(O), NH, O, C(O)NH, NHC(O), N(C1-C3 alkyl), N(C1-C3 alkyl)C(O), C(O)N(C1-C3 alkyl) and C1-C3 alkylene; in some embodiments, R 22 Selected from single bonds, C(O), NH, C(O)NH, NHC(O), N(CH3), N(CH3)C(O) and C(O)N(CH3); and / or

[0080] n is 1; and / or

[0081] R 32 and R 42 Together with the carbon atoms attached to it, it forms And R 52 R 62 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Each heteroaryl group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; in some embodiments, R 52 R 62 and R 72 Each is independently selected from H, deuterium, halogen, C1-C3 alkyl, and C1-C3 alkoxy; or

[0082] R 42 and R 52 Together with the carbon atoms attached to it, it forms And R 32 R 62 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Each heteroaryl group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted, and in some embodiments, R32 R 62 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; or

[0083] R 52 and R 62 Together with the carbon atoms attached to it, it forms And R 32 R 42 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Each heteroaryl group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; in some embodiments, R 32 R 42 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; and / or

[0084] W 3 For N, W 4 For CH or W 3 For CH, W 4 Let N be the number of elements in the array.

[0085] In some embodiments, R1 is selected from N, CH, CF, C-Cl, C-Br, and C (C1-C6 alkyl), preferably N, CH, CF, or C-CH3; more preferably, R1 is selected from N, CF, C-Cl, C-Br, and C (C1-C6 alkyl); more preferably, R1 is selected from CF, C-Cl, C-Br, and C (C1-C3 alkyl); in some embodiments, it is CF; and / or

[0086] R2 is selected from N, CH, CF, C-Cl, C-Br, and C (C1-C6 alkyl), and in some embodiments is N, CH, CF, or C-CH3; in some embodiments, it is CH; and / or

[0087] R3 is selected from C1-C3 alkyl, C1-C3 alkoxy, and halogen-substituted C1-C3 alkyl groups; in some embodiments, R3 is selected from methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, or trifluoroethyl; in some embodiments, R3 is difluoroethyl; in some embodiments, R3 is CH2CHF2; and / or

[0088] R4 is selected from N, CH, CF, C-Cl, C-Br, C (C1-C6 alkyl), and C (C1-C6 alkoxy). In some embodiments, N, CH, CF, C-Cl, C-Br, or C-OCH3 is selected; and in some embodiments, CF is selected.

[0089] R5 is selected from N and CH, and in some embodiments, CH; and / or

[0090] R6 is selected from N, CH, CF, C-Cl, C-Br, C (C1-C6 alkyl), and C (C1-C6 alkoxy), and in some embodiments is N, CH, CF, C-Cl, C-Br, or C-OCH3; in some embodiments is CF; and / or

[0091] R7 is selected from N and CH, and in some embodiments, CH; and / or

[0092] R m8 Selected from hydrogen, halogens and C1-C6 alkyl groups, in some embodiments hydrogen, fluorine or methyl, in some embodiments hydrogen;

[0093] R m9 The components are selected from hydrogen, halogens, and C1-C6 alkyl groups; in some embodiments, they are hydrogen, fluorine, or methyl; and in some embodiments, they are hydrogen; and / or

[0094] R m10 Selected from hydrogen and C1-C6 alkyl groups, and in some embodiments, hydrogen; and / or

[0095] R m11 It is selected from hydrogen and C1-C6 alkyl groups, and in some embodiments, it is hydrogen or methyl, and in some embodiments, it is methyl.

[0096] In some implementation schemes, Selected from In some implementation schemes, for and / or

[0097] Selected from

[0098] In some implementations, when R1, R2 and R in equation III m9 When they are not simultaneously CH, CH, and H, the values ​​in Equation III are... Selected from unsubstituted or substituted by one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino.

[0099] When R1 and R2 in equation III are both CH, and R m9 When H is used, in equation III Selected from unsubstituted or substituted by one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino.

[0100] In some implementation schemes, when Selected from hour, Selected from

[0101] when for hour, Selected from

[0102] In some implementations, the PTM is selected from:

[0103] In some implementations, the CLM comprises a structure selected from the following:

[0104] In some implementations, the CLM is selected from:

[0105] Among them, W 1 W 2 W 3 W 4 W 5 W 6 W 11 R8, R9, R N R m R F R G R T R f R g R t R T1 R F1 R G1 R 32 R 42 R 52 R 62 R 72 The definitions of m3, m4, m31, m41, m5, and m6 are the same as those in the previous text;

[0106] R 1D R 1E R 1d R 1e Each occurrence is independently selected from C(R) m 2. NR m O and C(O); R m The definition is the same as above;

[0107] Each time m1, m9 and m10 appear, they are each an independent integer of 0, 1, 2, 3, 4 or 5, and m1 + m9 + m10 ≤ 5;

[0108] Each time m7, m11, and m12 appear, they are each an independent integer of 0, 1, 2, 3, 4, 5, or 6, and m7 + m11 + m12 ≤ 6;

[0109] In some implementation schemes, W 1 and W 2 Each independently for CR a R b And W 1 and W 2 At least one of them is C (=O);

[0110] W 3 and W 4 Each independently for CR m Or N, and W 3 and W 4 One of them is N;

[0111] W 5 W 6 Each occurrence is independently C(R) m )2;

[0112] R 1D R 1E R 1d R 1e Each occurrence is independently selected from C(R) m 2. NR m O and C(O);

[0113] R F R G R f R g R F1 R G1 Each occurrence is independently selected from C(R) m )2;

[0114] R T R t R T1 Each occurrence is independently represented by N;

[0115] R8, R9, R 32 R 42 R 52 R 62 R 72 R a R b R N R m Each time it appears, it is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl and cyano groups;

[0116] Each time m1, m9, and m10 appear, they are each an independent integer of 0, 1, 2, 3, 4, or 5, and m1 + m9 + m10 ≤ 5; preferably, each time m1, m9, and m10 appear, they are each an independent integer of 0, 1, or 2, and m1 + m9 + m10 ≤ 2, preferably m1 + m9 + m10 = 1, m1 + m9 + m10 = 2, or m1 + m9 + m10 = 0;

[0117] Each occurrence of m7, m11, and m12 is an independent integer of 0, 1, 2, 3, 4, 5, or 6, and m7 + m11 + m12 ≤ 6; preferably, each occurrence of m7, m11, and m12 is an independent integer of 0, 1, 2, or 3, and m7 + m11 + m12 ≤ 3, preferably m7 + m11 + m12 = 2 or m7 + m11 + m12 = 1;

[0118] Each occurrence of m3 and m4 is an independent integer of 0, 1, 2, 3, or 4; m3 and m4 are not both 0; m3 + m4 ≤ 5; in some implementations, m3 + m4 = 4, m3 + m4 = 3, or m3 + m4 = 2;

[0119] Each occurrence of m5 and m6 is an independent integer of 0, 1, 2, 3, or 4; in some implementations, m5+m6=3, m5+m6=2, or m5+m6=1;

[0120] m31 and m41 each appear independently as integers of 0, 1, 2, 3, or 4; m31 and m41 are not both 0; m31 + m41 ≤ 5; in some implementations, m31 + m41 = 4, m31 + m41 = 3, or m31 + m41 = 2; and

[0121] W 11 It is C (=O);

[0122] In some embodiments, the CLM includes a structure selected from formulas (IV-1A), (IV-1B), and (IV-1C), wherein:

[0123] W 1 For C (=O), W 2 CH2 or W 1 CH2, W 2 For C (=O); in some implementations, W 1 For C (=O), W 2 It is CH2;

[0124] W 5 W 6 Each occurrence is independently CH2, -CH (C1-C6 alkyl), and -C (C1-C6 alkyl)2; in some embodiments, W 5 CH2, W 6 It is CH2;

[0125] R8 and R9 are each independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, and hydroxyl; in some embodiments, R8 is H and R9 is H;

[0126] R 32 R42 R 52 and R 62 Each of the following groups, when appearing independently, is selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, and cyano, more preferably H, F, Cl, Br, methyl, methoxy, or cyano; and in some embodiments, R 32 R 42 R 52 and R 62 Each occurrence is independently represented by H;

[0127] R T Let N be the number of people in the group.

[0128] R F R G Each occurrence is independently selected from CH2, NH, O, and C(O); CH2 is preferred; m3 is 2; m4 is 2;

[0129] R 1D R 1E Each occurrence is CH; m7 is 0, m11 is 0, m12 is 1; or m7 is 2, m11 is 0, m12 is 0.

[0130] In some implementations, the CLM is selected from:

[0131] In some implementations, the CLM is selected from:

[0132] In some implementation schemes, B L Each occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, SO, SO2, NR L3 SO2NR L3 SONR L3 CONR L3 NR L3 CONR L4 NRL3 SO2NR L4 CO, CR L1 =CR L2 C≡C, SiR L1 R L2 P(O)R L1 P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 0-6 R groups. L1 and / or R L2 Group substitution; R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, C. 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic, O-aryl, O-heteroaryl, SC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, N(C) 3-8 cycloalkyl)2, N(C) 3-8 cycloalkyl)(C 1-8 Alkyl), NH-C 3-8 Heterocyclic groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8 Heterocyclic group)(C 1-8 Alkyl), NH-aryl, N(aryl) (C 1-8 Alkyl), NH-heteroaryl, N(heteroaryl) (C 1-8 Alkyl), OH, NH2, SH, SO2P(O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH-(C1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, CO-C 1-8 Alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C) 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C) 1-8 Alkyl)2, CONH-C 1-8 Alkyl, CON(C) 1-8 Alkyl)2, N(C) 1-8 Alkyl)CONH(C 1-8 Alkyl), N(C) 1-8 Alkyl)CON(C 1-8 Alkyl)2, NHCONH(C 1-8 Alkyl), NHCON (C 1-8 Alkyl)2, NHCONH2, N(C) 1-8 alkyl)SO2NH(C 1-8 Alkyl), N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 Alkyl), NH SO2N (C 1-8 Alkyl)2, and NH2SO2NH2, optionally, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl and C 5-10 Each heteroaryl group is independently substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl, and haloheteroaryl; and q is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

[0133] In some implementations, B L It is selected from one or more of the following structures: -O-, -S-, -SO-, -SO2-, -CH2-, -C(O)-, -NH-, -CH(CH3)-, -CH(CH2CH3)-, -C(CH3) 2-、-N(CH3)-、-N(CH2CH3)-、 in, This is the connection site.

[0134] In some implementations, L is selected from the following structures:

[0135] Covalent bond, -(CH2) j -、-(CH2) p -NH-(CH2) s -、-(CH2) y -NH-(CH2) j -NH-(CH2) s -、-(CH2) p -C(O)-(CH2) s -、-(CH2) p -O-(CH2) s -、-(CH2) y -C(O)-(CH2) j -C(O)-(CH2) s -、-(CH2) y -O-(CH2) j -O-(CH2) s -、-(CH2) y -O-(CH2) j -C(O)-(CH2) s -、-(CH2) p -NH-(CH2) y -O-(CH2) j -C(O)-(CH2) s -、

[0136] Each time j appears, it is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0137] k, s, p, and y are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0138] For connection sites of CLM or PTM;

[0139] In some embodiments, L is selected from covalent bonds, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)7-, -NH-(CH2)8-, -C(O)-NH-CH2-, -C(O)-NH-(CH2)2-, -C(O)-NH-(CH2)3-, -C(O)-NH-(CH2)4-, -C(O) )-NH-(CH2)5-, -C(O)-NH-(CH2)6-, -C(O)-NH-(CH2)7-, -C(O)-NH-(CH2)8-, -CH2-NH-, -(CH2)2-NH-, -(CH2)3-NH-, -(CH2)4-NH-, -(CH2)5-NH-, -( CH2)6-NH-, -(CH2)7-NH-, -(CH2)8-NH-, -NH-CH2-NH-, -NH-(CH2)2-NH-, -NH-(CH2)3-NH-, -NH-(CH2)4-NH-, -NH-(CH2)5-NH-, -NH-(CH2)6-NH-, -NH -(CH2)7-NH-, -NH-(CH2)8-NH-, -(CH2-CH2-O)-CH2-CH2-, -(CH2-CH2-O)2-CH2-CH2-, -(CH2-CH2-O)3-CH2-CH2-, -NH-(CH2-CH2-O)-CH2-CH2-, -NH -(CH2-CH2-O)2-CH2-CH2-, -NH-(CH2-CH2-O)3-CH2-CH2-, -C(O)-NH-(CH2-CH2-O)-CH2-CH2-, -C(O)-NH-(CH2-CH2-O)2-CH2-CH2-, -C(O)-NH-(CH2- CH2-O)3-CH2-CH2-, -(CH2-CH2-O)-CH2-CH2-NH-, -(CH2-CH2-O)2-CH2-CH2-NH-, -(CH2-CH2-O)3-CH2-CH2-NH-, -NH-(CH2-CH2-O)-CH2-CH2-NH-, - NH-(CH2-CH2-O)2-CH2-CH2-NH-, -NH-(CH2-CH2-O)3-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)2-CH2-CH2-NH-,-C(O)-NH-(CH2-CH2-O)3-CH2-CH2-NH-、-CH2-CH2-(O-CH2-CH2)-、-CH2-CH2-(O-CH2-CH2)2-、-CH2-CH2-(O-CH2-CH2)3-、-NH-CH2-CH2-(O-CH2-CH2)-、-NH-CH2-CH2-(O-CH2-CH2)2-、-NH-CH2-CH2-(O-CH2-CH2)3-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)2-、-C(O)-NH- CH2-CH2-(O-CH2-CH2)3-,-CH2-CH2-(O-CH2-CH2)-NH-,-CH2-CH2-(O-CH2-CH2)2-NH-,-CH2-CH2-(O-CH2-CH2)3-NH-,-NH-CH2-CH2-(O-CH2-CH2)-NH-,-NH-CH2-CH2-(O-CH2-CH2)2-NH-,-NH-CH2-CH2-(O-CH2-CH2)3-NH-,-NH-CH2-CH2-O-CH2-CH2-C(O)-,-C(O)-CH2-CH2-O-CH2-CH2-NH-,-NH-(CH2) 4-C(O)-,-NH-(CH2)5-C(O)-,-NH-(CH2)6-C(O)-,-C(O)-(CH2)4-NH-,-C(O)-(CH2)5-NH-,-C(O)-(CH2)6-NH-,-NH-(CH2-CH2-O)-(CH2)3-,-NH-(CH2-CH2-O)-(CH2)4-,-NH-(CH2-CH2-O)-(CH2)5-,-NH-(CH2-CH2-O)-(CH2)6-,-(CH2)3-(O-CH2-CH2)-NH-,-(CH2)4-(O-CH2-CH2)-NH-,-(CH2)5-(O-C H2-CH2)-NH-,-(CH2)6-(O-CH2-CH2)-NH-,-CH2-CH2-O-(CH2)2-C(O)-,-CH2-CH2-O-(CH2)3-C(O)-,-CH2-CH2-O-(CH2)4-C(O)-,-C(O)-(CH2)2-O-CH 2-CH2-, -C(O)-(CH2)3-O-CH2-CH2-, -C(O)-(CH2)4-O-CH2-CH2-, -C(O)-(CH2)2-, -C(O)-(CH2)3-, -C(O)-(CH2)4-, -C(O)-(CH2)5-, -C(O)-(CH2)6--(CH2)2-C(O)-, -(CH2)3-C(O)-, -(CH2)4-C(O)-, -(CH2)5-C(O)-, -(CH2)6-C(O)-, -C(O)-(CH2)2-C(O)-, -C( O)-(CH2)3-C(O)-, -C(O)-(CH2)4-C(O)-, -C(O)-(CH2)5-C(O)-, -C(O)-(CH2)6-C(O)-, -CH2-C(O)-CH2-, -CH2- C(O)-(CH2)2-, -CH2-C(O)-(CH2)3-, -CH2-C(O)-(CH2)4-, -(CH2)2-C(O)-CH2-, -(CH2)2-C(O)-(CH2)2-, -(CH 2)2-C(O)-(CH2)3-, -(CH2)2-C(O)-(CH2)4-, -(CH2)3-C(O)-CH2-, -(CH2)3-C(O)-(CH2)2-, -(CH2)3-C(O)-(CH 2)3-, -(CH2)3-C(O)-(CH2)4-, -(CH2)4-C(O)-CH2-, -(CH2)4-C(O)-(CH2)2-, -(CH2)4-C(O)-(CH2)3-, -(CH2) 4-C(O)-(CH2)4-, -CH2-O-CH2-, -CH2-O-(CH2)2-, -CH2-O-(CH2)3-, -CH2-O-(CH2)4-, -(CH2)2-O-CH2-, -(CH2) 2-O-(CH2)2-, -(CH2)2-O-(CH2)3-, -(CH2)2-O-(CH2)4-, -(CH2)3-O-CH2-, -(CH2)3-O-(CH2)2-, -(CH2)3-O-(C H2)3-, -(CH2)3-O-(CH2)4-, -(CH2)4-O-CH2-, -(CH2)4-O-(CH2)2-, -(CH2)4-O-(CH2)3-, -(CH2)4-O-(CH2)4-,

[0140] In some implementations, L is selected from the following structures:

[0141] In another aspect of this disclosure, a compound of formula (Ⅱ-1) is provided:

[0142] CLM1―L1―PTM1(Ⅱ-1),

[0143] Or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates,

[0144] in:

[0145] PTM1 includes the structure shown in equation (Ⅲ-1):

[0146] In formula (Ⅲ-1), R1 is selected from N, CH, CF, C-Cl, C-Br and C (C1-C6 alkyl);

[0147] R2 is selected from N, CH, CF, C-Cl, C-Br and C (C1-C6 alkyl);

[0148] R3 is selected from C1-C3 alkyl, C1-C3 alkoxy, and halogen-substituted C1-C3 alkyl;

[0149] R4 is selected from N, CH, CF, C-Cl, C-Br, C (C1-C6 alkyl) and C (C1-C6 alkoxy);

[0150] R5 is selected from N and CH;

[0151] R6 is selected from N, CH, CF, C-Cl, C-Br, C (C1-C6 alkyl) and C (C1-C6 alkoxy);

[0152] R7 is selected from N and CH;

[0153] R m8 Selected from hydrogen, halogens, and C1-C6 alkyl groups;

[0154] R m9 Selected from hydrogen, halogens, and C1-C6 alkyl groups;

[0155] R m10 Selected from hydrogen and C1-C6 alkyl groups;

[0156] R m11 Selected from hydrogen and C1-C6 alkyl groups;

[0157] The condition is that R1, R2, and R m9 They are not simultaneously CH, CH, and H;

[0158] CLM1 includes structures selected from the following:

[0159] Among them, W 1 For C (=O), W 2 CH2 or W1 CH2, W 2 It is C (=O);

[0160] W 5 W 6 Each occurrence is independently CH2, CH(C1-C6 alkyl), and C(C1-C6 alkyl)2;

[0161] R8 and R9 are each independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy and hydroxyl groups;

[0162] R 32 R 42 R 52 and R 62 Each time it appears, it is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy and cyano, more preferably H, F, Cl, Br, methyl, methoxy or cyano;

[0163] R T Let N be the number of people in the group.

[0164] R F R G Each occurrence is independently selected from CH2, NH, O, and C(O); m3 is 2; m4 is 2;

[0165] R 1D R 1E Each occurrence is CH; m7 is 0, m11 is 0, m12 is 1; or m7 is 2, m11 is 0, m12 is 0;

[0166] The definition of L1 is the same as that of L as defined above. In some implementation schemes, L1 is selected from...

[0167] In some embodiments, R1 is selected from CF, C-Cl, C-Br and C (C1-C3 alkyl); preferably CF; and / or

[0168] R2 is selected from N, CH, CF, and C-CH3, preferably CH; and / or

[0169] R3 is selected from methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, or trifluoroethyl; in some embodiments, R3 is difluoroethyl; in some embodiments, R3 is CH2CHF2; and / or

[0170] R4 is N, CH, CF, C-Cl, C-Br, or C-OCH3, preferably CF; and / or

[0171] R5 is CH; and / or

[0172] R6 is N, CH, CF, C-Cl, C-Br, or C-OCH3, preferably CF; and / or

[0173] R7 is CH; and / or

[0174] R m8 It is H, F, Cl, Br, I, or methyl, preferably hydrogen; and / or

[0175] R m9 It is H, F, Cl, Br, I, or methyl, preferably hydrogen; and / or

[0176] R m10 It is hydrogen and C1-C3 alkyl, preferably hydrogen; and / or

[0177] R m11 Selected from hydrogen and C1-C6 alkyl groups, preferably hydrogen or methyl, more preferably methyl; and / or

[0178] W 1 For C (=O), W 2 CH2; and / or

[0179] W 5 CH2, W 6 CH2; and / or

[0180] R8 is H, R9 is H; and / or

[0181] R 32 R 42 R 52 and R 62 Each time it appears, it is independently selected from H, F, Cl, Br, methyl, methoxy, and cyano; in some embodiments, R 32 R 42 R 52 and R 62 Each occurrence is independently H; and / or

[0182] R T For N; and / or

[0183] R F R G For CH2; m3 is 2; m4 is 2; and / or

[0184] R 1D R 1E Each occurrence is CH; m7 is 0, m11 is 0, m12 is 1; or m7 is 2, m11 is 0, m12 is 0.

[0185] In another aspect of this disclosure, a compound of formula (IA) is provided.

[0186] Or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates,

[0187] In the formula, X1 is N or CH; X2 is N or CH; X3 is N or CH;

[0188] q1 is 0 or 1; q2 is 0, 1 or 2;

[0189] R3 is selected from fluoroethyl, difluoroethyl and trifluoroethyl;

[0190] R m9 Selected from hydrogen, halogens, and C1-C6 alkyl groups;

[0191] R m10 Selected from hydrogen and C1-C6 alkyl groups;

[0192] R m11 Selected from hydrogen, methyl, ethyl, and isopropyl;

[0193] R4 is selected from N, CH, CF, C-Cl, C-Br, C (C1-C6 alkyl) and C (C1-C6 alkoxy);

[0194] R5 is either N or CH;

[0195] R6 is selected from N, CH, CF, C-Cl, C-Br, C(C1-C6 alkyl), and C(C1-C6 alkoxy).

[0196] R7 is either N or CH;

[0197] CLM includes structures selected from those shown in Equations (IV-1a), (IV-1b), and (IV-1c):

[0198] Among them, W 1 For C (=O), W 2 For CH or W 1 For CH, W 2 For C (=O); in some implementations, W 1 For C (=O), W 2 For CH;

[0199] R 32 R 42 R 52 and R 62 Each of the following groups is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, and cyano, preferably H, F, Cl, Br, methyl, methoxy, or cyano;

[0200] R F R G Each occurrence is independently selected from CH2, NH, O, and C(O); CH2 is preferred; m3 is 2; m4 is 2;

[0201] R 1D R 1E Each occurrence is CH; m7 is 0, m11 is 0, m12 is 1; or m7 is 2, m11 is 0, m12 is 0.

[0202] In some embodiments, the compound is selected from:

[0203] Another aspect of this disclosure provides a compound comprising the structure shown in formula (I') that binds to an estrogen receptor protein:

[0204] Or its pharmaceutically acceptable salt;

[0205] In the formula, R ER0’ It is a leaving group;

[0206] R1, R2, R3, R4, R5, R6, R7, R m8 R m9 R m10 and R m11 Each definition is the same as above;

[0207] R ER0’ Selected from -(CR) ERa R ERb ) n1 R ERc Methanesulfonate group (Ms), trifluoromethanesulfonate group (Tf), p-toluenesulfonyl chloride group (TsCl), p-benzenemethylsulfonate group (Ts), -C(O)OR ERd and -OC(O)R ERd ;

[0208] R ERa R ERb R ERc and R ERd Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, hydroxyl, nitro, cyano, amino and -ON=NH, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl are optionally substituted by one or more substituents independently selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, carboxyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and amino;

[0209] n1 is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0210] In some implementation schemes, R ER0’ Selected from Cl, Br, I, methoxy, hydroxy, nitro, amino, -OC(O)CH3, -ON=NH, OTf, O-Br, Ms, Tf, Ts, TsCl, C(O)OCH3, C(O)OCH3, CH2NO2, CH2ON=NH and CH2NH2;

[0211] In some implementation schemes, Selected from More preferably and / or

[0212] Selected from

[0213] Among them, when R1, R2 and R in equation III m9 When they are not simultaneously CH, CH, and H, the values ​​in Equation III are... Selected from unsubstituted or substituted by one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino.

[0214] When R1 and R2 in equation III are both CH, and R m9When H is used, in equation III Selected from unsubstituted or substituted by one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino.

[0215] In some implementation schemes, when Selected from hour, Selected from

[0216] when for hour, Selected from

[0217] Another aspect of this disclosure provides a compound that binds to an estrogen receptor protein, having the structure shown in Formula I-1:

[0218] Among them, R ER0 Selected from -(CR) ERa R ERb ) n1 R ERc Methanesulfonate group (Ms), trifluoromethanesulfonate group (Tf), p-toluenesulfonyl chloride group (TsCl), p-benzenemethylsulfonate group (Ts), -C(O)OR ERd and -OC(O)R ERd ;

[0219] R ERa R ERb R ERc and R ERd Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, hydroxyl, nitro, cyano, amino and -ON=NH, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl are optionally substituted by one or more substituents independently selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, carboxyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and amino;

[0220] n1 is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0221] R ER1 and R ER2 Each is independently selected from N or CR ERm ;

[0222] R ER3 -N(R) ERm31 )-;

[0223] R ERm31 The group is selected from H, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally separated by 1, 2, 3, 4, or 5 atoms, each independently selected from carboxyl, deuterium, halogen, C Substituents of 1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; in some embodiments, R ERm31 for

[0224] R ER4 Selected from -N- and -C(R) ERm4 )-;

[0225] R ER5 Selected from -N- and -C(R) ERm5 )-;

[0226] R ER6 Selected from -N- and -C(R) ERm6 )-;

[0227] R ER7 Selected from -N- and -C(R) ERm7 )-;

[0228] R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 R ERm6 R ERm7 R ER8 R ER9 RER10 and R ER11 Each time it appears, it is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; in some embodiments, R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 R ERm6 R ERm7 R ER8 R ER9 R ER10 and R ER11 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; or

[0229] R ERm4 and R ERm5 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S. The saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloyl group, C6-C 10 The aryl group is substituted with one or more substituents of a 5-10 membered heteroaryl group; in some embodiments, R ERm4 and R ERm5 The atom to which it is attached is capable of forming a saturated or unsaturated 5-7 membered cycloalkyl group or a 5-7 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the saturated or unsaturated 5-7 membered cycloalkyl group or the 5-7 membered heterocycloalkyl group is unsubstituted or optionally substituted with one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, and amino; or

[0230] R ERm6 and R ERm7The carbon atom to which it is attached is capable of forming a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, C6-C 10 Aryl, C5-C 10 The substituent is a heteroaryl group and one or more substituents of a 5-10 membered heteroaryl group; in some embodiments, R ERm6 and R ERm7 The carbon atom to which it is attached can form a saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocycloalkyl, wherein the saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocycloalkyl is unsubstituted or is optionally substituted by one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino.

[0231] And when R ER1 R ER2 Both are CH, and R ER9 When it is H, R ERm4 and R ERm5 The atoms to which they are attached form saturated or unsaturated ring structures; or, R ERm6 and R ERm7 And the atoms they are connected to form saturated or unsaturated ring structures, or R ER4 and R ER5 One of them is selected from N; or R mm R m8 and R m9 At least one of them is not H in each occurrence;

[0232] In some implementation schemes, R mm and R m9 Each occurrence must have at least one value that is not H.

[0233] In some implementations, when R ER1 R ER2、 and R ER9 When they are not simultaneously CH, CH and H, respectively, in Equation I Selected from unsubstituted or substituted with one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino.

[0234] When R ER1 R ER2 Both are CH, and R ER9 When H is , when, in Equation I Selected from unsubstituted or substituted with one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino.

[0235] Another aspect of this disclosure provides a compound that binds to an estrogen receptor protein, having the structure shown in Formula I-2:

[0236] Among them, R ER0 Selected from -(CR) ERa R ERb ) n1 R ERc Methanesulfonate group (Ms), trifluoromethanesulfonate group (Tf), p-toluenesulfonyl chloride group (TsCl), p-benzenemethylsulfonate group (Ts), -C(O)OR ERd and -OC(O)R ERd ;

[0237] R ERa R ERb R ERc and R ERd Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, hydroxyl, nitro, cyano, amino and -ON=NH, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl are optionally substituted by one or more substituents independently selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, carboxyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and amino;

[0238] n1 is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10;

[0239] R ER1 and R ER2 Each is independently selected from N or CR ERm ;

[0240] R ER3 -N(R) ERm31 )-;

[0241] R ERm31 The group is selected from H, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally separated by 1, 2, 3, 4, or 5 atoms, each independently selected from carboxyl, deuterium, halogen, C Substituents of 1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; in some embodiments, R ERm31 for

[0242] R ER4 Selected from -N- and -C(R) ERm4 )-;

[0243] R ER5 Selected from -N- and -C(R) ERm5 )-;

[0244] R ER6 Selected from -N- and -C(R) ERm6 )-;

[0245] R ER7 Selected from -N- and -C(R) ERm7 )-;

[0246] R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 R ERm6 R ERm7 R ER8 R ER9 R ER10 and R ER11Each time it appears, it is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; in some embodiments, R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 R ERm6 R ERm7 R ER8 R ER9 R ER10 and R ER11 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; or

[0247] R ERm4 and R ERm5 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S. The saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloyl group, C6-C 10 The aryl group is substituted with one or more substituents of a 5-10 membered heteroaryl group; in some embodiments, R ERm4 and R ERm5 The atom to which it is attached is capable of forming a saturated or unsaturated 5-7 membered cycloalkyl group or a 5-7 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the saturated or unsaturated 5-7 membered cycloalkyl group or the 5-7 membered heterocycloalkyl group is unsubstituted or optionally substituted with one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, and amino; or

[0248] R ERm6 and R ERm7The carbon atom to which it is attached is capable of forming a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, C6-C 10 Aryl, C5-C 10 The substituent is a heteroaryl group and one or more substituents of a 5-10 membered heteroaryl group; in some embodiments, R ERm6 and R ERm7 The carbon atom to which it is attached can form a saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocycloalkyl, wherein the saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocycloalkyl is unsubstituted or is optionally substituted by one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino.

[0249] And when R ER1 R ER2 Both are CH, and R ER9 When it is H, R ERm4 and R ERm5 The atoms to which they are attached form saturated or unsaturated ring structures; or, R ERm6 and R ERm7 And the atoms they are connected to form saturated or unsaturated ring structures, or R ER4 and R ER5 One of them is selected from N; or R mm R m8 and R m9 At least one of them is not H in each occurrence;

[0250] In some implementation schemes, R mm and R m9 Each occurrence must have at least one value that is not H.

[0251] In some implementations, when R ER1 R ER2 and R ER9 When they are not simultaneously CH, CH and H, weight 1 in 3-1-6, in Equation I Selected from unsubstituted or substituted with one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino.

[0252] Dangdang R ER1 R ER2 Both are CH, and R ER9 When H is , when, in Equation I Selected from unsubstituted or substituted with one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino.

[0253] In some implementation schemes, it is selected from:

[0254] In another aspect of this disclosure, a compound of formula (Ⅳ') is provided:

[0255] CLM―L―A L2 (Ⅳ')

[0256] Or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates,

[0257] In the formula, CLM and L are as defined in any of the previous implementation schemes;

[0258] A L2 Independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C2-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups;

[0259] In some implementation schemes, A L2 Selected from

[0260] In another aspect of this disclosure, a compound of formula IV is provided, the compound having the following structure

[0261] CLM-La(Formula IV)

[0262] Or it may be its isomer, isotope derivative, polymorph, prodrug, or a pharmaceutically acceptable salt or solvate thereof.

[0263] in:

[0264] La is -(B) L ) q -A L2 ;

[0265] A L2 Independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C2-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The B group is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups; L , q, and CLM are as defined in any of the preceding implementation schemes.

[0266] In some embodiments, the compound is selected from the following structures:

[0267] This disclosure also provides the use of the compounds described above or pharmaceutically acceptable salts thereof in the preparation of medicaments for degrading estrogen receptor proteins.

[0268] This disclosure also provides a pharmaceutical composition comprising any of the compounds described above and at least one pharmaceutically acceptable carrier.

[0269] This disclosure also provides the use of the foregoing compound or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, or the foregoing pharmaceutical compositions in the preparation of a medicament for treating or preventing a disease; wherein the disease is a disease treated by degrading estrogen receptor proteins or a disease associated with the accumulation and / or aggregation of estrogen receptor proteins.

[0270] In some embodiments, the disease is cancer, preferably breast cancer, ductal carcinoma of the breast, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myeloid monocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer; in some embodiments, the breast cancer is ER. + Breast cancer, in some embodiments, has a Y537S or D538G mutation.

[0271] This disclosure also provides methods for treating or preventing diseases, comprising administering to a subject in need a therapeutically effective amount of the aforementioned compound or isomers thereof, isotopic derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, or pharmaceutical compositions thereof; wherein the disease is a disease treated by degrading estrogen receptor proteins or a disease associated with the accumulation and / or aggregation of estrogen receptor proteins.

[0272] In some embodiments, the condition is cancer, preferably breast cancer, ductal carcinoma of the breast, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myeloid monocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer; in some embodiments, the breast cancer is ER+ breast cancer, and in some embodiments, the breast cancer has a Y537S or D538G mutation.

[0273] This disclosure also provides the compounds described above or their isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, or pharmaceutical compositions described above for the treatment or prevention of diseases; wherein the disease is a disease treated by degrading estrogen receptor proteins or a disease associated with the accumulation and / or aggregation of estrogen receptor proteins.

[0274] In some embodiments, the disease is cancer, preferably breast cancer, ductal carcinoma of the breast, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myeloid monocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer; in some embodiments, the breast cancer is ER. + Breast cancer, in some embodiments, has a Y537S or D538G mutation.

[0275] Another aspect of this disclosure provides a compound of formula IA, the compound having the following structure:

[0276] CLM―La (Formula IA)

[0277] Or it may be its isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate.

[0278] in:

[0279] CLM is selected from the following structures:

[0280] W 1 and W 2 Whether they are the same or different, each is independently a CR. a R b Or C(O), and W 1 and W 2 At least one of them is C(O);

[0281] W 5 and W 6 Each occurrence is independently C(R) m )2;

[0282] R 1D R 1E R F and R G Each occurrence is independently C(R) m 2. NR m C(O), O or S;

[0283] R T For N or CR 2h ;

[0284] Z is CR a Or N;

[0285] R 32 R 42 R 62 R m and R 2hEach of the following groups is independently selected from H, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, alkenyl, alkynylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; in some embodiments, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl and 5-10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-10-membered heterocyclic, C6-C 10 The aryl and 5-10-membered heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, halogenated C1-C6 alkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, 4-10-membered heterocyclic groups, and C6-C6 heterocyclic groups. 10 The aryl group is substituted with one or more substituents of a 5-10 membered heteroaryl group; in some embodiments, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C10 Aryl and C5-C 10 Each heteroaryl group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocyclic, C6-C 10 The aryl group is substituted with one or more substituents of 5-10 heteroaryl groups; and in some embodiments, R 32 R 42 R 62 R 2h and R m Each time it appears, it is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and hydroxyl; further, in some embodiments, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C3 alkyl, deuterated C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, halo-C1-C3 alkoxy, and hydroxyl; further, in some embodiments, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, hydroxyl, and C1-C3 alkoxy; further, in some embodiments, R 32 R 42 R 62 R 2h and R m Each time it appears, it is independently selected from H, F, Cl, Br, I, C1-C3 alkyl and C1-C3 alkoxy groups;

[0286] Each time m7, m11, and m12 appear, they are each an independent integer of 0, 1, 2, 3, 4, 5, or 6, and m7 + m11 + m12 ≤ 6;

[0287] m3 and m4 each appear independently as integers of 0, 1, 2, 3 or 4; m3 and m4 are not both 0; m3 + m4 ≤ 5;

[0288] R8 is selected from H, halogens, deuterium atoms, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, cycloalkyl, C1-C6 haloalkyl, and hydroxyalkyl; in some embodiments, R8 is selected from H, halogens, deuterium atoms, C1-C3 alkyl, and hydroxyl; and in even more embodiments, R8 is selected from H, deuterium atoms, F, Cl, Br, I, C1-C3 alkyl, and hydroxyl.

[0289] R9, R a and R b Each is independently selected from H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy;

[0290] La is -(B) L ) q -A L2 ;

[0291] B L Each occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, S(O), S(O)2, NR L3 S(O)2NR L3 S(O)NR L3 C(O)NR L3 NR L3 C(O)NR L4 NR L3 S(O)2NR L4 C(O), CR L1 =CR L2 C≡C, SiR L1 R L2 P(O)R L1 P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 Monocyclic alkyl groups, monoheterocyclic alkyl groups, bridged cycloyl groups, and spirocyclic cycloyl groups, wherein the monocyclic alkyl groups, monoheterocyclic alkyl groups, bridged cycloyl groups, and spirocyclic cycloyl groups are optionally surrounded by 0, 1, 2, 3, 4, 5, or 6 R groups. L1 and / or R L2 Group substitution; in some embodiments, B L Each occurrence is independently selected from: CR L1 R L2 O, S, SO, SO2, NR L3C(O), C≡C, 3-8 membered monocyclic alkylene, 3-8 membered monocyclic heterocyclic group containing 1-3 heteroatoms independently selected from N, O and S, 5-15 membered bridged cyclic group containing 0-5 heteroatoms independently selected from N, O and S, and 5-15 membered spirocyclic group containing 0-5 heteroatoms independently selected from N, O and S, wherein the 3-8 membered monocyclic alkylene, 3-8 membered monocyclic heterocyclic alkylene, 5-15 membered bridged cyclic group and 5-15 membered spirocyclic group are optionally separated by 0, 1, 2 or 3 R L1 and / or R L2 Group substitution;

[0292] R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, and C. 1-8 Alkyl, C 1-8 Alkoxy, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-1 1 heterocyclic group, C(O)-C 3-8 Cycloalkyl, C(O)-C 3-11 Heterocyclic groups, SC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, N(C) 3-8 cycloalkyl)2, N(C) 3-8 cycloalkyl)(C 1-8 Alkyl), N(C) 1-8 Alkylene)(C 3-8 cycloalkyl), NH-C 3-8 Heterocyclic groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8 Heterocyclic group)(C 1-8 Alkyl groups, -OH groups, -NH2 groups, -SH groups, S(O)2P(O) (OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl group, -C≡CH, CH=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, C(O)-C 1-8 Alkyl, C(O)-OC 1-8 Alkyl, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, S(O)2NH-C 1-8 Alkyl, S(O)2N(C) 1-8 Alkyl)2、S(O)NH-C 1-8 Alkyl, S(O)N(C) 1-8 Alkyl)2、C(O)NH-C 1-8 Alkyl, C(O)NH-C 3-8 cycloalkyl, C(O)NH-C 3-11 Heterocyclic groups, C(O)N(C) 1-8 Alkyl)2, N(C) 1-8 alkyl)C(O)NH(C 1-8 Alkyl), N(C) 1-8 alkyl)C(O)N(C 1-8 Alkyl)2、NHC(O)NH(C 1-8 Alkyl), NHC(O)N(C 1-8 Alkyl)2, NHC(O)NH2, N(C) 1-8 alkyl)S(O)2NH(C 1-8 Alkyl), N(C) 1-8 alkyl)S(O)2N(C 1-8 Alkyl)2, NHS(O)2NH(C 1-8 Alkyl), NHS(O)2N(C 1-8 Alkyl)2 and NHS(O)2NH2, optionally, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic groups and C 3-8 Each heterocyclic group is independently substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, halocycloalkyl, haloheteroalkyl and alkylamino;

[0293] q is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and

[0294] A L2Independently selected from H, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, and C4-C 10 Heterocyclic groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, and C4-C 10 Each heterocyclic group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, and C4-C 10 One or more substituents in the heterocyclic group are substituted;

[0295] And when -(B L ) q -A L2 When the carbon chain structure does not contain rings, q is an integer of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;

[0296] When -(B) L ) q -A L2 When a monocyclic structure is contained, and the number of monocyclic structures is 1, the monocyclic structure is a C3-C8 heterocyclic alkyl group containing 1-3 N atoms;

[0297] -(B L ) q -A L2 It is not H, -CH3, or -C(O)-CH3.

[0298] In another aspect of this disclosure, a compound of formula IA-1 is provided, the compound having the following structure:

[0299] CLM-La(Formula I)

[0300] Or it may be its isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate.

[0301] in:

[0302] CLM is selected from the following structures:

[0303] W 1 and W 2 Whether they are the same or different, each is independently a CR. a R bOr C (=O), and W 1 and W 2 At least one of them is C (=O);

[0304] W 5 W 6 Each occurrence is independently C(R) m )2;

[0305] R 1D R 1E R F and R G Each occurrence is independently C(R) m 2. NR m C (=O), O or S;

[0306] R T For N or CR 2h ;

[0307] R 32 R 42 R 62 R m and R 2h Each of the following groups is independently selected from H, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, alkenyl, alkynylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; in some embodiments, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Each heteroaryl group is independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; in some embodiments, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Each heteroaryl group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; in some embodiments, R 32 R 42 R 62 R 2h and R m Each time it appears, it is independently selected from H, deuterium, F, Cl, Br, I, and C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy and hydroxyl groups; further, in some embodiments, R32 R 42 R 62 R 2h and R m Each time it appears, it is independently selected from H, deuterium, F, Cl, Br, I, and C. 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy and hydroxyl groups, in some embodiments, R 32 R 42 R 62 R 2h and R m Each time it appears, it is independently selected from H, F, Cl, Br, I, C. 1-3 Alkyl, hydroxyl and C 1-3 Alkoxy; in some embodiments, R 32 R 42 R 62 R 2h and R m Each time it appears, it is independently selected from H, F, Cl, Br, I, and C. 1-3 alkyl;

[0308] Each time m7, m11, and m12 appear, they are each an independent integer of 0, 1, 2, 3, 4, 5, or 6, and m7 + m11 + m12 ≤ 6;

[0309] Each occurrence of m3 and m4 is an independent integer of 0, 1, 2, 3, or 4; m3 and m4 are not both 0; m3 + m4 ≤ 5;

[0310] R8 is selected from H, halogens, deuterium atoms, C1-C6 alkyl, C1-C6 alkoxy, hydroxyl, cycloalkyl, C1-C6 haloalkyl, and hydroxyalkyl; in some embodiments, R8 is selected from H, halogens, deuterium atoms, C1-C3 alkyl, and hydroxyl; in some embodiments, R8 is selected from H, deuterium atoms, F, Cl, Br, I, C1-C3 alkyl, and hydroxyl.

[0311] R9, R a and R b Each is independently selected from H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy;

[0312] La is -(B) L ) q -A L2 ;

[0313] B LEach occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, S(O), S(O)2, NR L3 S(O)2NR L3 S(O)NR L3 C(O)NR L3 NR L3 C(O)NR L4 NR L3 S(O)2NR L4 C(O), CR L1 =CR L2 C≡C, SiR L1 R L2 P(O)R L1 P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 Monocyclic alkyl groups, monoheterocyclic alkyl groups, bridged cycloalkyl groups, and spirocyclic cycloalkyl groups, wherein the monocyclic alkyl groups and monoheterocyclic cycloalkyl groups are optionally surrounded by 0, 1, 2, 3, 4, 5, or 6 R groups. L1 and / or R L2 Group substitution; in some embodiments, B L Each occurrence is independently selected from: CR L1 R L2 O, S, SO, SO2, NR L3 , CO, C≡C, 3-8 membered monocyclic alkylene, 3-8 membered monoheterocyclic alkylene containing 1-3 heteroatoms independently selected from N, O and S, 5-15 membered bridged cycloylene containing 0-5 heteroatoms independently selected from N, O and S, and 5-15 membered spirocyclic cycloylene containing 0-5 heteroatoms independently selected from N, O and S, wherein the 3-8 membered monocyclic alkylene, 3-8 membered monocyclic alkylene, 5-15 membered bridged cycloylene and 5-15 membered spirocyclic cycloylene are optionally separated by 0, 1, 2 or 3 R L1 and / or R L2 Group substitution;

[0314] R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, and C. 1-8 Alkyl, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -NH-C 1-8 Alkyl, N(C)1-8 Alkyl)2, C 3-11 cycloalkyl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, CO-C 3-8 cycloalkyl, CO-C 3-11 Heterocyclic groups, SC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, N(C) 3-8 cycloalkyl)2, N(C) 3-8 cycloalkyl)(C 1-8 Alkyl), N(C) 1-8 Alkylene)(C 3-8 cycloalkyl), NH-C 3-8 Heterocyclic groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8 Heterocyclic group)(C 1-8 Alkyl), OH, NH2, SH, SO2P(O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, CO-C 1-8 Alkyl, COO-C 1-8 Alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C) 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C) 1-8 Alkyl)2, CONH-C 1-8 Alkyl, CONH-C 3-8 cycloalkyl, CONH-C 3-11 Heterocyclic groups, CON(C) 1-8 Alkyl)2, N(C) 1-8 Alkyl)CONH(C 1-8 Alkyl), N(C) 1-8 Alkyl)CON(C 1-8 Alkyl)2, NHCONH(C 1-8 Alkyl), NHCON (C1-8 Alkyl)2, NHCONH2, N(C) 1-8 alkyl)SO2NH(C 1-8 Alkyl), N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 Alkyl), NHSO2N(C 1-8 Alkyl)2, and NHSO2NH2, optionally, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl and C 3-11 Each heterocyclic group is independently replaced by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, halocycloalkyl, haloheteroalkyl and alkylamino;

[0315] q is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and

[0316] A L2 Independently selected from H, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, and C4-C 10 Heterocyclic groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, and C4-C 10 Each heterocyclic group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, and C4-C 10 One or more substituents in the heterocyclic group are substituted;

[0317] And when -(B L ) q -A L2 When the carbon chain structure does not contain rings, q is an integer of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;

[0318] When -(B) L ) q -A L2When a monocyclic structure is contained and the number of ring structures is 1, the monocyclic structure is a C3-C8 heterocyclic alkyl group containing 1-3 N atoms;

[0319] -(B L ) q -A L2 It is not H, -CH3, or -C(O)-CH3.

[0320] In some implementation schemes,

[0321] W 1 and W 2 Each independently for CR a R b And W 1 and W 2 At least one of them is C (=O); and / or

[0322] W 5 and W 6 Each occurrence is independently C(R) m )2; and / or

[0323] R 1D and R 1E Each occurrence is independently selected from C(R) m 2. NR m O and CO; and / or

[0324] R F and R G Each occurrence is independently selected from C(R) m )2; and / or

[0325] R T For N; and / or

[0326] Z is CH or N; and / or

[0327] R8, R9, R 32 R 42 R 62 R a R b and R m Each occurrence is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, and hydroxyl; and / or

[0328] Each occurrence of m7, m11, and m12 is an independent integer of 0, 1, 2, 3, 4, 5, or 6, and m7 + m11 + m12 ≤ 6; preferably, each occurrence of m7, m11, and m12 is an independent integer of 0, 1, 2, or 3, and m7 + m11 + m12 ≤ 3, preferably m7 + m11 + m12 = 2 or m7 + m11 + m12 = 1; and / or

[0329] Each time m3 and m4 appear, they are each an independent integer of 0, 1, 2, 3, or 4; m3 and m4 are not both 0; and m3+m4=4, m3+m4=3, or m3+m4=2.

[0330] In some implementations, the CLM is selected from:

[0331] In some implementations, where B L Selected from one or more of the following structures: -O-, -S-, -SO-, -SO2-, -CH2-, -CO-, -NH-, -C≡C-, -CH(CH3)-, -CH(CH2CH3)-, -C(CH3)2-, -N(CH3)-, -N(CH2CH3)-,

[0332] This is the connection point.

[0333] In some implementations, where -(B L ) q -Selected from the following structures:

[0334] Covalent bond, -(CH2) j -、-(CH2) p -NH-(CH2) s -、-(CH2) y -NH-(CH2) j -NH-(CH2) s -、-(CH2) p -CO-(CH2) s -、-(CH2) p -O-(CH2) s -、-(CH2) y -CO-(CH2) j -CO-(CH2) s -、-(CH2) y -O-(CH2) j -O-(CH2) s -、-(CH2) y-O-(CH2) j -CO-(CH2) s -、-(CH2) p -NH-(CH2) y -O-(CH2) j -CO-(CH2) s -、

[0335] Each time j appears, it is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

[0336] k, s, p, and y are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0337] For connection points with CLM or PTM;

[0338] In some implementations, -(B L ) q - Selected from covalent bonds, -(CH2)2-OCH2CH2-, -(CH2)2-(OCH2CH2)2-, -(CH2)2-(OCH2CH2)3-, -(CH2)2-(OCH2CH2)4, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-(CH2)9-, -NH-(CH2) 10 -、-NH-(CH2) 11 -、-NH-(CH2) 12 -、-NH-(CH2) 13 -、-NH-(CH2) 14 -、-NH-(CH2) 15-NH-CH2-,-NH-(CH2)2-,-NH-(CH2)3-,-NH-(CH2)4-,-NH-(CH2)5-,-NH-(CH2)6-,-NH-(CH2)7-,-NH-(CH2)8-,-C(O)-NH-CH2-,-C(O)-NH-(CH2)2-,-C(O)-NH-(CH2)3-,-C(O)-NH-(CH2)4-,-(CH2)4-C(O)-NH-(CH2)4-,-(CH2)2-C(O)-NH-(CH2)3-,-(CH2)5-C(O)-NH-(CH2)8-,-C(O)-NH-(CH2) 2)5-,-C(O)-NH-(CH2)6-,-C(O)-NH-(CH2)7-,-C(O)-NH-(CH2)8-,-CH2-NH-,-(CH2)2-NH-,-(CH2)3-NH-,-(CH2)4-NH-,-(CH2)5-NH-,-(CH2)6-NH-,-(CH2)7-NH-,-(CH2)8-NH-,-NH-CH2-NH-,-NH-(CH2)2-NH-,-NH-(CH2)3-NH-,-NH-(CH2)4-NH-,-NH-(CH2)5-NH-,-NH-(CH2)6-NH-,-NH-(CH2 )7-NH-,-NH-(CH2)8-NH-,-(CH2-CH2-O)-CH2-CH2-,-(CH2-CH2-O)2-CH2-CH2-,-(CH2-CH2-O)3-CH2-CH2-,-NH-(CH2-CH2-O)-CH2-CH2-,-NH-(CH2-CH2-O)2-CH2-CH2-,-NH-(CH2-CH2-O)3-CH2-CH2-,-C(O)-NH-(CH2-CH2-O)-CH2-CH2-,-C(O)-NH-(CH2-CH2-O)2-CH2-CH2-,-C(O)-NH-(CH2-CH 2-O)3-CH2-CH2-、-(CH2-CH2-O)-CH2-CH2-NH-、-(CH2-CH2-O)2-CH2-CH2-NH-、-(CH2-CH2-O)3-CH2-CH2-NH-、-NH-(CH2-CH2-O)-CH2-CH2-NH-、-NH-(CH2-CH2-O)2-CH2-CH2-NH-、-NH-(CH2-CH2-O)3-CH2-CH2-NH-、-C(O)-NH-(CH2-CH2-O)-CH2-CH2-NH-、-C(O)-NH-(CH2-CH2-O)2-CH2-CH2-NH-、-C(O)-NH-(CH2-CH2-O)3-CH2-CH2-NH-、-CH2-CH2-(O-CH2-CH2)-、-CH2-CH2-(O-CH2-CH2)2-、-CH2-CH2-(O-CH2-CH2)3-、-NH-CH2-CH2-(O-CH2-CH2)-、-NH-CH2-CH2-(O-CH2-CH2)2-、-NH-CH2-CH2-(O-CH2-CH2)3-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)2-、-C(O)-NH- CH2-CH2-(O-CH2-CH2)3-,-CH2-CH2-(O-CH2-CH2)-NH-,-CH2-CH2-(O-CH2-CH2)2-NH-,-CH2-CH2-(O-CH2-CH2)3-NH-,-NH-CH2-CH2-(O-CH2-CH2)-NH-,-NH-CH2-CH2-(O-CH2-CH2)2-NH-,-NH-CH2-CH2-(O-CH2-CH2)3-NH-,-NH-CH2-CH2-O-CH2-CH2-C(O)-,-C(O)-CH2-CH2-O-CH2-CH2-NH-,-NH-(CH2) 4-C(O)-,-NH-(CH2)5-C(O)-,-NH-(CH2)6-C(O)-,-C(O)-(CH2)4-NH-,-C(O)-(CH2)5-NH-,-C(O)-(CH2)6-NH-,-NH-(CH2-CH2-O)-(CH2)3-,-NH-(CH2-CH2-O)-(CH2)4-,-NH-(CH2-CH2-O)-(CH2)5-,-NH-(CH2-CH2-O)-(CH2)6-,-(CH2)3-(O-CH2-CH2)-NH-,-(CH2)4-(O-CH2-CH2)-NH-,-(CH2)5-(O-C H2-CH2)-NH-,-(CH2)6-(O-CH2-CH2)-NH-,-CH2-CH2-O-(CH2)2-C(O)-,-CH2-CH2-O-(CH2)3-C(O)-,-CH2-CH2-O-(CH2)4-C(O)-,-C(O)-(CH2)2-O-CH 2-CH2-, -C(O)-(CH2)3-O-CH2-CH2-, -C(O)-(CH2)4-O-CH2-CH2-, -C(O)-(CH2)2-, -C(O)-(CH2)3-, -C(O)-(CH2)4-, -C(O)-(CH2)5-, -C(O)-(CH2)6--(CH2)2-C(O)-, -(CH2)3-C(O)-, -(CH2)4-C(O)-, -(CH2)5-C(O)-, -(CH2)6-C(O)-, -C(O)-(CH2)2-C(O)-, -CO-(CH2)3-C(O)-, -C(O)-(CH2)4-C(O)-, -C(O)-(CH2)5-C(O)-, -C(O)-(CH2)6-C(O)-, -CH2-C(O)-CH2-, -CH2-C(O)-(CH2)2-, -CH2-C(O)-(CH2)3-, -CH2-C(O)-(CH2)4-, -(CH2)2-C(O)-CH2-, -(CH2)2-C(O)-(CH2)2-, -(CH2)2-C(O)-(CH2)3-, -(CH2)2-C(O)-(CH2)4-, -(CH2)3-C(O)-CH2-, -(CH2)3-C(O)-(CH2)2-, -(CH2)3-C(O)-(CH2)3-, -(CH2)3-C(O)-(CH2)4-, -(CH2)4-C(O)-CH2-, -(CH2)4-C(O)-(CH2)2-, -(CH2)4-C(O)-(CH2)3-, -(CH2)4-C(O-)(CH2)4-, -CH2-O-CH2-, -CH2-O-(CH2)2-, -CH2-O-(CH2)3-, -CH2-O-(CH2)4-, -(CH2)2-O-CH2-, -(CH2)2-O-(CH2)2-, -(CH2)2-O-(CH2)3-, -(CH2)2-O-(CH2)4-, -(CH2)3-O-CH2-, -(CH2)3-O-(CH2)2-, -(CH2)3-O-(CH2)3-, -(CH2)3-O-(CH2)4-, -(CH2)4-O-CH2-, -(CH2)4-O-(CH2)2-, -(CH2)4-O-(CH2)3-, -(CH2)4-O-(CH2)4-

[0339] In some embodiments, -(B L ) q- Selected from covalent bonds, -(CH2)5-, -(CH2)8-, -NH-(CH2)5-, -NH-(CH2)8-, -NH-(CH2) 13 -, -NH-(CH2)2-OCH2CH2-, -NH-(CH2)2-(OCH2CH2)2-, -NH-(CH2)2-(OCH2CH2)4-, -NH-( CH2)4-C(O)-NH-(CH2)7-, -NH-(CH2)3-C(O)-NH-(CH2)3-, -NH-(CH2)2-C(O)-NH-CH2-,

[0340] In some implementations, it is selected from the following structure:

[0341] Another aspect of this disclosure provides the use of a compound of Formula IV in the preparation of a medicament for treating diseases or conditions mediated by simultaneously degrading estrogen receptor protein and IKZF2 protein, or for treating diseases or conditions mediated by estrogen receptor protein and IKZF2, said compound having the following chemical structure:

[0342] CLM―L―PTM(Form IV);

[0343] Or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates thereof, wherein:

[0344] L is a bond that covalently connects the CLM and the PTM, or -(B L ) q -;

[0345] B L Each occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, S(O), S(O)2, NR L3 S(O)2NR L3 S(O)NR L3 C(O)NR L3 NRL3 C(O)NR L4 NR L3 S(O)2NR L4 C(O), CR L1 =CR L2 C≡C, SiR L1 R L2 P(O)R L1 P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 Cycloalkylene, heterocyclic, aryl, and heteroaryl, wherein the cycloalkylene, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 0-6 R groups. L1 and / or R L2 Group substitution; in some embodiments, B L Each occurrence is independently selected from: CR L1 R L2 O, S, S(O), S(O)2, NR L3 C(O), C≡C, 3-16-membered cycloalkylene, 3-16-membered heterocyclic, 6-10-membered arylene, and 5-10-membered heteroarylene, wherein the 3-16-membered cycloalkylene, 3-16-membered heterocyclic, 6-10-membered arylene, and 5-10-membered heteroarylene are optionally surrounded by 0, 1, 2, or 3 R's. L1 and / or R L2 Group substitution;

[0346] R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, C. 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, C(O)-C 3-8 Cycloalkyl, C(O)-C 3-11 Heterocyclic groups, OC 6-10 Aryl, O-5-10 heteroaryl, SC 3-8 cycloalkyl, NH-C3-8 cycloalkyl, N(C) 3-8 cycloalkyl)2, N(C) 3-8 cycloalkyl)(C 1-8 Alkyl), N(C) 1-8 Alkylene)(C 3-8 cycloalkyl), NH-C 3-8 Heterocyclic groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8 Heterocyclic group)(C 1-8 Alkyl), NH-C 6-10 Aryl, N(C) 6-10 Aryl)(C 1-8 Alkyl), NH-5-10 heteroaryl, N(5-10 heteroaryl) (C 1-8 Alkyl groups, -OH groups, -NH2 groups, -SH groups, S(O)2P(O) (OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, C(O)-C 1-8 Alkyl, C(O)-OC 1-8 Alkyl, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, S(O)2NH-C 1-8 Alkyl, S(O)2N(C) 1-8 Alkyl)2、S(O)NH-C 1-8 Alkyl, S(O)N(C) 1-8 Alkyl)2、C(O)NH-C 1-8 Alkyl, C(O)NH-C 3-8 cycloalkyl, C(O)NH-C 3-11 Heterocyclic groups, C(O)N(C) 1-8 Alkyl)2, N(C) 1-8 alkyl)C(O)NH(C 1-8 Alkyl), N(C) 1-8 alkyl)C(O)N(C 1-8 Alkyl)2、NHC(O)NH(C 1-8 Alkyl), NHC(O)N(C 1-8Alkyl)2, NHC(O)NH2, N(C) 1-8 alkyl)S(O)2NH(C 1-8 Alkyl), N(C) 1-8 alkyl)S(O)2N(C 1-8 Alkyl)2, NHS(O)2NH(C 1-8 Alkyl), NHS(O)2N(C 1-8 Alkyl)2 and NHS(O)2NH2, optionally, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic group, C 3-8 Heterocyclic group, C 6-10 The aryl and 5-10 heteroaryl groups are each independently substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl, and haloheteroaryl; in some embodiments, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups are each independently selected from F, Cl, Br, I, C. 1-6 The substance is substituted by one or more substituents selected from alkyl, methoxy, and ethoxy groups;

[0347] q is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;

[0348] Preferably:

[0349] B L The definitions of q and q are the same as those defined in any previous implementation scheme;

[0350] The definition of CLM is the same as that defined in any previous implementation scheme; and

[0351] PTM is a portion of an estrogen receptor protein that binds to it; wherein, the PTM is selected from the following structural formulas:

[0352] R1 and R2 are each independently selected from N and CR. m ;

[0353] R3, each time it appears, is independently selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally replaced by 1, 2, 3, 4, or 5 atoms, each independently selected from carboxyl, deuterium, ... Halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl and C1-C6 alkylaminoacyl substituents; in some embodiments, R3 is

[0354] Each occurrence of R4 is independently selected from N and CRm4;

[0355] Each occurrence of R5 is independently selected from N and CRm5;

[0356] Each occurrence of R6 is independently selected from N and CRm6;

[0357] Each occurrence of R7 is independently selected from N and CRm7;

[0358] R m8 Selected from -N(R) a )2 and -OR a ;R m9 Selected from -C(R) a )3、-N(R a )2、-OR a and R a ;or

[0359] R m8 With R m9 Forming a ring structure;

[0360] R m8 and R m9 The bonded carbon atoms form saturated or unsaturated C4-C bonds. 10 The subcyclic hydrocarbon group or a 4-10 membered subheterocyclic group containing 1-3 heteroatoms each independently selected from N, O, and S, wherein the saturated or unsaturated C4-C 10 The cyclic hydrocarbon group or 4-10 membered heterocyclic group is unsubstituted or optionally selected from oxo (=O), F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocyclic group, C6-C10 The aryl group is substituted with one or more substituents of a 5-10 membered heteroaryl group; in some embodiments, R m8 and R m9 The carbon atom to which it is attached forms a saturated or unsaturated C5-C7 subcyclic hydrocarbon group or a 5-7 membered subheterocyclic group containing 1-3 heteroatoms, each independently selected from N, O, and S. The saturated or unsaturated C5-C7 subcyclic hydrocarbon group or the 5-7 membered subheterocyclic group is unsubstituted or optionally substituted with one or more substituents selected from oxo (=O), F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, oxo, and amino. In some embodiments, R... m8 and R m9 The carbon atom to which it is attached forms a saturated or unsaturated C5-C7 subcyclic hydrocarbon group or a 5-7 membered subheterocyclic group containing one or two N atoms, wherein the saturated or unsaturated C5-C7 subcyclic hydrocarbon group or the 5-7 membered heterocyclic group is unsubstituted or optionally substituted by one or more substituents selected from oxo (=O), F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano and amino;

[0361] Q is selected independently from CR each time it appears. 11 and N;

[0362] Q 1 Each occurrence is O, S, or NR. 11 ;

[0363] Q 2 Each occurrence is either O or CR 11 ;

[0364] R a R m R m1 R m2 R m3 R m4 R m5 R m6 R m7 R 10 R 11 R p1 R p2 and R p3Each occurrence is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; in some embodiments, R a R m R m1 R m2 R m3 R m4 R m5 R m6 R m7 R 10 R 11 R p1 R p2 and R p3 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, and amino;

[0365] R 12 Each time it appears, it is independently selected from hydroxyl and carboxyl groups;

[0366] m13, m14, and m15 are each independently selected from 0, 1, 2, 3, 4, and 5; and

[0367] Each time p appears, it is independently selected from 0, 1, and 2;

[0368] Indicates a single bond or a double bond;

[0369] Preferably:

[0370] B L Each occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, S(O), S(O)2, NR L3 S(O)2NR L3 S(O)NR L3 C(O)NR L3 NR L3 C(O)NR L4 NR L3 S(O)2NR L4 C(O), CR L1 =CR L2 C≡C, SiRL1 R L2 P(O)R L1 P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 Cycloalkylene, heterocyclic, aryl, and heteroaryl, wherein the cycloalkylene, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 0-6 R groups. L1 and / or R L2 Group substitution;

[0371] R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, C. 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, OC 6-10 Aryl, O-5-10 heteroaryl, SC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, N(C) 3-8 cycloalkyl)2, N(C) 3-8 cycloalkyl)(C 1-8 Alkyl), NH-C 3-8 Heterocyclic groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8 Heterocyclic group)(C 1-8 Alkyl), NH-C 6-10 Aryl, N(C) 6-10 Aryl)(C 1-8 Alkyl), NH-5-10 heteroaryl, N(heteroaryl) (C 1-8 Alkyl groups, -OH, -NH2, -SH, SO2P(O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 Alkyl), C(C)1-8 Alkyl)=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, C(O)-C 1-8 Alkyl, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, S(O)2NH-C 1-8 Alkyl, S(O)2N(C) 1-8 Alkyl)2、S(O)NH-C 1-8 Alkyl, S(O)N(C) 1-8 Alkyl)2、C(O)NH-C 1-8 Alkyl, C(O)N(C) 1-8 Alkyl)2, N(C) 1-8 alkyl)C(O)NH(C 1-8 Alkyl), N(C) 1-8 alkyl)C(O)N(C 1-8 Alkyl)2、NHC(O)NH(C 1-8 Alkyl), NHC(O)N(C 1-8 Alkyl)2, NHC(O)NH2, N(C) 1-8 alkyl)S(O)2NH(C 1-8 Alkyl), N(C) 1-8 alkyl)S(O)2N(C 1-8 Alkyl)2, NHS(O)2NH(C 1-8 Alkyl), NHS(O)2N(C 1-8 Alkyl)2, and NHS(O)2NH2, optionally, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic group, C 3-8 Heterocyclic group, C 6-10 The aryl and 5-10 heteroaryl groups are each independently substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxyl, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloyl, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl and haloheteroaryl;

[0372] q is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20;

[0373] The definition of CLM is the same as that defined in any previous implementation scheme; and

[0374] PTM is the estrogen receptor protein moiety. In some embodiments, PTM is selected from the following structural formulas:

[0375] R1 and R2 are each independently selected from N and CR. m ,

[0376] R3 is selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally replaced by 1, 2, 3, 4, or 5 atoms, each independently selected from carboxyl, deuterium, halogen, C Substituents of 1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxy, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; in some embodiments, R3 is...

[0377] Each occurrence of R4 is independently selected from N or CRm4;

[0378] Each occurrence of R5 is independently selected from N or CRm5;

[0379] Each occurrence of R6 is independently selected from N or CRm6;

[0380] Each occurrence of R7 is independently selected from N or CRm7;

[0381] R m8 Selected from -N(R) a )2 and -0R a ;

[0382] R m9 Selected from -C(R) a )3、-N(R a )2、-0R a and R a ;or

[0383] R m8 With R1 or R m9 Forming a ring structure; when R1 and R m8 When R1 forms a ring structure with the atoms it is connected to, R1 is C, and R1 and R m8It forms a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycle containing 1-3 heteroatoms each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or 4-10 membered heterocycle is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 The aryl group is substituted with one or more substituents of a 5-10 membered heteroaryl group; in some embodiments, R1 and R2 are substituted with one or more substituents of a aryl group and a 5-10 membered heteroaryl group. m8 The atom to which it is attached forms a saturated or unsaturated 5-7 membered cycloalkyl group or a 5-7 membered heterocyclic group containing 1-3 heteroatoms, each independently selected from N, O, and S. The saturated or unsaturated 5-7 membered cycloalkyl group or 5-7 membered heterocyclic group is unsubstituted or optionally substituted by one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, and amino. In some embodiments, R1 and R... m8 The bonded atom forms a saturated or unsaturated 5-7 membered heterocyclic group containing one or two N heteroatoms, wherein the saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocyclic group is unsubstituted or substituted by one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; or

[0384] R m8 and R m9 The attached carbon atom forms a saturated or unsaturated 4-10 membered carbocyclic group or a 4-10 membered heterocyclic group containing 1-3 heteroatoms each independently selected from N, O, and S. The saturated or unsaturated 4-10 membered carbocyclic group or 4-10 membered heterocyclic group is unsubstituted or optionally selected from oxo, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 The aryl group is substituted with one or more substituents of a 5-10 membered heteroaryl group; in some embodiments, R m8 and R m9The carbon atom to which it is attached forms a saturated or unsaturated 5-7 membered carbocyclic group or a 5-7 membered heterocyclic group containing 1-3 heteroatoms, each independently selected from N, O, and S. The saturated or unsaturated 5-7 membered carbocyclic group or the 5-7 membered heterocyclic group is unsubstituted or optionally substituted with one or more substituents selected from oxo, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, oxo, and amino groups. In some embodiments, R... m8 and R m9 It forms a saturated or unsaturated 5-7 membered heterocyclic group containing one or two N heteroatoms with the attached carbon atom, wherein the saturated or unsaturated 5-7 membered carbocyclic group or 5-7 membered heterocyclic group is unsubstituted or is optionally substituted by one or more substituents selected from oxo, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino.

[0385] Each time Q appears, it is selected independently from CR. 11 and N;

[0386] Q 1 Each occurrence is O, S, or NR. 11 ;

[0387] R a R m R m1 R m2 R m3 R m4 R m5 R m6 R m7 R 10 R 11 R p1 R p2 and R p3 Each occurrence is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, C1-C6 alkylaminoacyl; in some embodiments, R a R m R m1 R m2 R m3 R m4 R m5 R m6R m7 R 10 R 11 R p1 R p2 and R p3 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino; and

[0388] m13, m14, and m15 are each independently selected from 0, 1, 2, 3, 4, and 5.

[0389] In some implementations, the PTM is selected from:

[0390] In some embodiments, the compound is selected from:

[0391] In some embodiments, the compound is selected from:

[0392] This disclosure also provides a pharmaceutical composition comprising the foregoing compound and a pharmaceutically acceptable excipient.

[0393] This disclosure also provides a method for degrading IKZF2 protein in a subject or biological sample, comprising administering the aforementioned compound to a subject or contacting a biological sample with the aforementioned compound.

[0394] This disclosure also provides the use of the compounds or pharmaceutical compositions described above in the preparation of a medicament for degrading IKZF2 protein in a subject or biological sample.

[0395] This disclosure also provides the use of the compounds or pharmaceutical compositions described above for degrading IKZF2 protein in a subject or biological sample.

[0396] This disclosure also provides a method for treating or preventing a disease or condition in a subject in need, comprising administering the aforementioned compound or pharmaceutical composition to the subject.

[0397] This disclosure also provides the use of the compounds or pharmaceutical compositions described above in the preparation of a medicament for treating or preventing a disease or condition in a subject in need.

[0398] This disclosure also provides the use of the compounds or pharmaceutical compositions described above for the treatment or prevention of a disease or condition in a subject in need.

[0399] In some implementations, the disease or condition is an IKZF2-mediated disease or condition.

[0400] This disclosure also provides a method for treating a disease or condition in a subject of need by simultaneously degrading estrogen receptor protein and IKZF2 protein, or for treating or preventing a disease or condition mediated by estrogen receptor protein and / or IKZF2 in a subject of need, comprising administering to the subject a compound represented by Formula IV as described above.

[0401] This disclosure also provides a compound of formula IV described above for treating or preventing a disease or condition in a subject of need by simultaneously degrading estrogen receptor protein and / or IKZF2 protein, or for treating or preventing a disease or condition mediated by estrogen receptor protein and / or IKZF2 in a subject of need.

[0402] In some of these embodiments, the condition is a tumor or cancer, preferably breast cancer, ductal carcinoma of the breast, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myeloid monocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, or cervical cancer.

[0403] Definition and detailed explanation

[0404] In this invention, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the related terms and laboratory procedures used herein are all widely used terms and routine procedures in the respective fields. To better understand this invention, definitions and explanations of related terms are provided below.

[0405] In the description herein, references to “some embodiments,” “some implementations,” or “some implementation schemes” describe a subset of all possible embodiments. However, it is understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0406] As used herein and unless otherwise stated, the terms “comprising,” “including,” “having,” “containing,” and their grammatical equivalents, including their grammatical equivalents, should generally be understood as open-ended and non-restrictive, e.g., not excluding other unlisted elements or steps.

[0407] In this specification and the claims reported herein, the phrase “and / or” is interpreted as meaning “any one or both” of the elements, that is, the elements may exist together in some cases or the elements may exist separately in other cases.

[0408] When listing a range of values, it is assumed that each value and the subranges within that range are included. For example, "C 1-6 Alkyl groups include C1, C2, C3, C4, C5, C6, and C6. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0409] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any usable connection point. The substituents are preferably selected independently from one or more substituents chosen from H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0410] The term "heteroalkyl" refers to an alkyl group in which one or more -CH2- atoms are substituted by heteroatoms selected from NH, O, and S, or where one or more -CH- atoms are substituted by N atoms; wherein the alkyl group is as defined above; the heteroalkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any usable connection point, wherein the substituent is preferably independently selected independently from one or more substituents selected from H atoms, D atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, hydroxy groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0411] The term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon substituent, which can be monocycloalkyl, bicycloalkyl, bridged cycloalkyl, or spirocycloalkyl, etc.; the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, and even more preferably 4 to 7 carbon atoms. Non-limiting examples of monocycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc. Cycloalkyl can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable connection point, wherein the substituent is preferably independently selected independently from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0412] "Spirocycloalkyl" refers to a polycyclic hydrocarbon group formed by two or more monocyclic rings sharing a single carbon atom (called a spiro atom). Based on the number of shared spiro atoms between the rings, spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl, and polyspirocycloalkyl groups. Preferably, they are 6 to 14 quinary elements (C1 to C2). 6-14 Spirocycloalkyl, more preferably 7 to 11 quinary (C) 7-11 Spirocycloalkyl groups. Specific examples of spirocycloalkyl groups include, but are not limited to:

[0413] The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein the definition of alkyl or cycloalkyl is as described herein. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more substituents independently selected from H atom, D atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0414] The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups, independently selected from one or more substituents selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0415] The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in its molecule, wherein the alkyl group is defined as described above. The alkynyl group can be substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl substituents.

[0416] The term "heterocyclic group" or "heterocyclic alkyl group" refers to a saturated or partially unsaturated cyclic hydrocarbon substituent, which can be monocyclic, bicyclic, bridged, or spirocyclic, etc.; it contains 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon, but the ring portion does not include -OO-, -OS-, or -SS-. The heterocyclic group preferably contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms, wherein 1 to 3 are heteroatoms; even more preferably, it contains 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms; and even more preferably, it contains 5 or 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, azahexacyclobutyl, oxohexacyclobutyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.

[0417] The term "spirocyclic heterocyclic group" or "spirocyclic heterocyclic alkyl group" refers to a polycyclic heterocyclic group formed by two or more saturated or partially unsaturated monocyclic rings sharing a single carbon atom (called a spiro atom), wherein one or more (e.g., 1, 2, or 3) ring atoms are selected from nitrogen, oxygen, or S (=O). mThe spirocyclic group consists of a heteroatom (where m' is an integer from 0 to 2), with the remaining ring atoms being carbon. When the heteroatom is nitrogen, it can be substituted or unsubstituted (i.e., N or NR, where R is hydrogen or another substituent as defined herein). Each monocycle may contain one or more double bonds, but no ring has a fully conjugated π-electron system. Spirocyclic groups are classified as monospirocyclic, bispirocyclic, or polyspirocyclic groups based on the number of shared spiro atoms between rings. Preferably, they are “5 to 20-membered spirocyclic heterocycles”, having 5 to 20 ring atoms, wherein one of the shared spiro atoms is a 3 to 8-membered monocyclic heterocyclic ring, and the other is a 3 to 8-membered monocyclic heterocyclic ring or a 3 to 8-membered monocyclic cycloalkyl ring. Specific examples of spirocyclic heterocycles include, but are not limited to: These spirocyclic groups can be connected to the rest of the molecule by any suitable ring atom (preferably a nitrogen atom).

[0418] The heterocyclic group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0419] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. Aryl groups can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable connection point, preferably independently selected independently from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0420] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered), more preferably 5- or 6-membered, such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl group can be substituted or unsubstituted; when substituted, the substituent can be substituted at any usable linking point, preferably independently selected by one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0421] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0422] The term "hydroxyalkyl" refers to an alkyl group that is substituted with one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0423] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0424] The term "amino" refers to -NH2.

[0425] The term "cyano" refers to -CN.

[0426] The term "nitro" refers to -NO2.

[0427] The term "leaving group" refers to an atom or group (which may be charged or uncharged) that has detached from an atom or molecule, which is considered to be a remnant or major part of the molecule involved in a specific reaction, such as a nucleophilic substitution reaction. Representative leaving groups include trifluoromethanesulfonates; chlorine, bromine, and iodine; sulfonate groups, such as methanesulfonates, toluenesulfonates, p-bromobenzenesulfonates, p-toluenesulfonates, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.

[0428] The term "ubiquitin ligase" refers to a family of proteins that facilitate the transfer of ubiquitin to specific substrate proteins, targeting those proteins for degradation. For example, cerebellar proteins are E3 ubiquitin ligase proteins, alone or in combination with E2 ubiquitin-binding enzymes, that cause ubiquitin to attach to a lysine residue on a target protein and subsequently target a specific protein substrate for degradation via the proteasome. Therefore, E3 ubiquitin ligases, alone or in combination with E2 ubiquitin-binding enzymes, are the cause of ubiquitin transfer to the target protein. Generally, ubiquitin ligases participate in polyubiquitination, where a second ubiquitin is attached to a first ubiquitin, a third ubiquitin to a second ubiquitin, and so on. Polyubiquitinated proteins are used for degradation via the proteasome. However, there are some ubiquitination events limited to monoubiquitination, where only a single ubiquitin is added to the substrate molecule via a ubiquitin ligase. Monoubiquitinated proteins are not targeted to the proteasome for degradation but may instead be altered in their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin. Complicating matters further, different lysine residues on ubiquitin can be targeted by E3 to prepare chains. The most common lysine is Lys48 on the ubiquitin chain. This is the lysine used to prepare polyubiquitin, and it is recognized by the proteasome.

[0429] The term "target protein" refers to proteins and peptides that have any biological function or activity (including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction). In some implementations, target proteins include structural proteins, receptors, enzymes, cell surface proteins, and proteins involved in integrated cellular functions, including proteins involved in: catalytic activity, aromatase activity, motility activity, helicase activity, metabolic processes (anabolism and catabolism), antioxidant activity, proteolysis, biosynthesis, proteins with kinase activity, oxidoreductase activity, transferase activity, hydrolase activity, lyase activity, isomerase activity, ligase activity, enzyme regulator activity, signal transduction factor activity, structural molecule activity, binding activity (proteins, lipids, carbohydrates), receptor activity, cell motility, membrane fusion, cell communication, regulation of biological processes, development, cell differentiation, stimulation response, behavioral proteins, cell adhesion proteins, proteins involved in cell death, proteins involved in transport (including protein transport activity, nuclear transport, ion transport activity, channel transport activity, carrier activity), permease activity, secretory activity, electron transport activity, pathogens, associated protein regulator activity, nucleic acid binding activity, transcription regulator activity, extracellular structure and biological origin activity, and translation regulator activity. The proteins include proteins derived from eukaryotes and prokaryotes, which include microorganisms, viruses, fungi, and parasites, as well as numerous others, including humans, microorganisms, viruses, fungi, and parasites that are targets for drug therapy, other animals including domestic animals, microorganisms and other antimicrobial drugs used to determine the targets of antibiotics, plants, and even viruses, as well as numerous others.

[0430] "Optional" or "optionally" means that the event or situation described below may but does not have to occur, and the description includes the circumstances in which the event or situation occurs or does not occur. For example, "optionally substituted cyclopropyl" means that the cyclopropyl group may be substituted but is not required to be present, and the description includes the cases where the cyclopropyl group is substituted and the cases where the cyclopropyl group is not substituted.

[0431] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine possible or impossible substitutions without much effort (through experiment or theory).

[0432] The term "one or more" refers to one or more under reasonable conditions, such as two, three, four or five.

[0433] Unless otherwise stated, use The absolute configuration representing the center of a solid. (Used as...) Represents the relative configuration of the solid center; key Including possible Configuration, as long as it is chemically permissible. In It refers to the junction of chemical bonds.

[0434] "Pharmaceutically acceptable salt" means a salt of the compounds disclosed herein that is safe and effective when used in mammals and has the intended biological activity. Specific Implementation

[0435] The following examples pertain to the intermediate compounds and final products identified in the specification and synthetic regimens. The preparation of the compounds of the present invention is described in detail using the following examples, but the described chemical reactions are disclosed in accordance with their general applicability to the preparation of the compounds of the present invention. Sometimes, the reactions may not be applicable to every compound within the scope of the present invention as described. Compounds in which this may occur will be readily identifiable to those skilled in the art. In these cases, the reactions can be successfully carried out with conventional modifications known to those skilled in the art.

[0436] The starting materials, chemical reagents, and solvents used in this invention are all commercially available and were purchased from companies such as Anaiji Chemical, Shanghai Bide Pharmaceutical, Beijing Innocare, Jiangsu Aikon, Sinopharm Group, Beijing Bailingwei, and Yunnan Xinlanjing.

[0437] The structures of all compounds synthesized in this application were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS).

[0438] Nuclear magnetic resonance (NMR) measurements were performed using a Bruke AVANCE-400 / 600 NMR spectrometer. The deuterated solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0439] Mass spectrometry (MS) measurements were performed using Waters Acquity Plus device implementation.

[0440] High-performance liquid chromatography (HPLC) preparation was carried out using a Waters 2489 system.

[0441] The medium-pressure rapid preparative chromatograph is a COMBIFLASH NEXTGEN 300+.

[0442] The thin-layer chromatography silica gel plates used are Silica gel 60 thin-layer chromatography silica gel plates (aluminum plates, containing fluorescence).

[0443] The silica gel (100-200 mesh, 200-300 mesh) used in silica gel thin-layer chromatography was purchased from Inokai.

[0444] The reaction process in the examples was detected using thin-layer chromatography (TLC). The systems used to monitor the developing solvent and the eluent used to purify the compounds by column chromatography included: petroleum ether / ethyl acetate system and dichloromethane / methanol system.

[0445] This invention uses the following PROTAC synthesis formula to synthesize the compounds listed in the table below:

[0446] PROTAC Synthesis Formula ER-TT-1

[0447] Wherein: R1 is selected from F or methyl, R2 is selected from F or methyl, and R3 is selected from H or methyl.

[0448] PROTAC Synthesis Formula ER-TT-2

[0449] Wherein: R1 is selected from F or methyl, etc., and R2 is selected from F or methyl, etc.

[0450] The preparation processes for the two exemplary compounds of the general formula are as follows:

[0451] Preparation of ER-P-19

[0452] The synthesis steps are as follows:

[0453] Step 1: Synthesis of compound ER-P-19-2

[0454] At room temperature, compound ER-P-19-1 (100 g, 0.51 mol, 1.0 eq.) and Heptane:Toluene = 1:1 (0.8 L) were added to a 2 L reaction flask and stirred. At room temperature, p-toluenesulfonic acid pyridinium salt (2.55 g, 0.01 mol, 0.02 eq.) was added to the reaction system. After the addition was complete, 3,4-dihydropyran (0.15 L, 1.62 mol, 3.2 eq.) was added dropwise. After the addition was complete, the reaction flask was transferred to a 40 °C oil bath and stirred for 12 h. After the reaction was complete, 5 wt% NaHCO3 aqueous solution (0.5 L) was added to the system. The mixture was separated, and the upper organic phase was washed twice with 5 wt% NaHCO3 aqueous solution, then once with H2O. The organic phase was concentrated until the system showed a brown oily substance. Heptane (0.08 L) was added to the system and transferred to an ice bath at -5 °C with stirring. The mixture was then filtered and the filter cake was washed with Heptane. The filter cake was dried at room temperature for 2 h to obtain ER-P-19-2 (101 g, 71.2%), a white solid.

[0455] 1 H NMR (400MHz, Methanol-d4) δ8.39(d,J=0.9Hz,1H),7.62(dt,J=8.6,0.9Hz,1H),7.29(d,J=7.1Hz,1H),7.21(dd,J=8.6,7.2Hz,1H),5.73(dd,J=8. 5,4.0Hz,1H),4.13(dq,J=11.5,2.5Hz,1H),3.83(td,J=11.2,3.0Hz,1H) ,2.20(ddd,J=9.7,8.7,4.3Hz,2H),2.10–2.02(m,1H),1.89–1.63(m,3H).

[0456] LCMS(ESI):[M+H] + =281.15

[0457] Step 2: Synthesis of compound ER-P-19-3

[0458] At room temperature, compound ER-P-19-2 (100 g, 0.36 mol, 1.0 eq.) and THF (0.8 L) were added to a 3 L three-necked flask. The flask was purged with nitrogen, and the system was cooled to 0–5 °C. LDA (2.0 M in Heptane, 0.19 L, 0.37 mol, 1.05 eq.) was added dropwise. After the addition was complete, the temperature was maintained at 0–5 °C, and the mixture was stirred for 1 h. The system temperature was then maintained at -40–-20 °C, and NFSI (123.37 g, 0.39 mol, 1.1 eq.) was added in five portions. After the addition was complete, the temperature was maintained at -40 °C, and the mixture was stirred for 1 h. The temperature was then maintained at -30 °C–-20 °C. Once the reaction was complete, 5% NaOH aqueous solution (1 L, 10 V) was slowly added dropwise to the reaction system. After the addition was complete, MTBE (0.5 L) was added to the system, and the mixture was stirred. The mixture was separated, and the lower aqueous phase was extracted twice with MTBE. Combine the organic phases, wash them once with saturated NaCl aqueous solution, concentrate and dry the organic phases. Add IPA to the system, stir continuously at room temperature for 12 h, filter, wash the filter cake with IPA, and dry the filter cake at room temperature to obtain a white solid ER-P-19-3 (45.36 g, 42.6%).

[0459] 1H NMR (400MHz, Methanol-d4) δ7.49(ddd,J=8.8,2.0,0.6Hz,1H),7.26(d,J=7.1Hz,1H),7.18(dd,J=8.8,7.2Hz,1H),5.81(ddd,J=9.9,2.7,1.1Hz,1H), 4.13–4.03(m,1H),3.81(ddd,J=11.5,10.6,3.0Hz,1H),2.51–2.36(m,1H) ,2.16(dtd,J=13.3,3.9,1.6Hz,1H),2.09–2.00(m,1H),1.91–1.62(m,3H).

[0460] Step 3: Synthesis of compound ER-P-19-5

[0461] At room temperature, ER-P-19-3 (100 g, 0.33 mol, 1.0 eq.) and THF (0.8 L) were added to a 3 L three-necked flask, purged with nitrogen, and cooled to -78 °C. n-BuLi (1.6 M in THF, 0.23 L, 0.37 mol, 1.1 eq.) was added dropwise, and the mixture was stirred for 1 h. At -78 °C to °C, ER-P-19-4 (103 g, 0.43 mol, 1.3 eq.) was dissolved in THF (0.5 L) and added dropwise to the reaction system. The mixture was stirred at room temperature for at least 2 h. The reaction was then complete. At 0 °C, a saturated NH4Cl aqueous solution was added dropwise to the reaction system, and the pH was adjusted to 2–3 by adding 2 M hydrochloric acid aqueous solution. The mixture was extracted twice with EA. The organic phases were combined, washed once with a saturated NaCl aqueous solution, and concentrated until a brown oily substance appeared. n-Heptane:EtOAc = 6:1 was added to the system, and the mixture was stirred overnight. After filtration, the filter cake was dried at room temperature for 2 hours to obtain a yellow solid ER-P-19-5 (59 g, 60.17%).

[0462] 1 H NMR (400MHz, DMSO-d6) δ12.45(s,1H),7.32–7.26(m,2H),6.90(d,J=6.5Hz,1H),6.80(d,J=8 .5Hz,1H),3.81(p,J=7.3Hz,1H),2.94(d,J=7.0Hz,2H),1.29(s,9H),1.04(d,J=6.7Hz,3H).

[0463] Step 4: Synthesis of compound ER-P-19-6

[0464] At room temperature, compound ER-P-19-5 (100 g, 0.34 mol, 1.0 eq.) and DCM (0.4 L) were added to a 2 L reaction flask. HCl (2 M in 1,4-dioxane, 0.7 L) was added dropwise to the system, and the mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was concentrated to obtain 102 g of crude ER-P-19-6.

[0465] 1 H NMR(400MHz,DMSO-d6)δ12.70(s,1H),7.41–7.34(m,2H),7.01(dd,J=4.5,3.3Hz,1H),3.32(d d,J=13.4,5.5Hz,2H),3.03(dd,J=13.4,9.2Hz,1H),1.29–1.16(m,2H),1.12(d,J=6.4Hz,3H).

[0466] LCMS(ESI):[M+H] + =194.25.

[0467] Step 5: Synthesis of compound ER-P-19-8

[0468] At room temperature, ER-P-19-6 (25 g, 65 mmol, 1.0 eq.) and 1,4-dioxane (252 mL) were added to a 1 L single-necked flask. DIEA (140 mL, 39 mmol, 6 eq.) and ER-P-19-7 (40 mL, 84 mmol, 1.3 eq.) were added to the system. The temperature was maintained at 80 °C, and the mixture was stirred for 1 h. After the reaction was complete, the mixture was evaporated to dryness, and the concentrate was slurried overnight with petroleum ether:ethyl acetate (2:1). The mixture was filtered, and the filter cake was washed with petroleum ether:ethyl acetate (2:1). The filtrate was concentrated to obtain a brown oily liquid, ER-P-19-8 (15 g, 45.1%).

[0469] 1 H NMR (400MHz, DMSO-d6) δ12.71(d,J=8.4Hz,1H),7.39(dd,J=4.3,1.3Hz,2H),7.02(dd,J=4.8,3.0Hz,1H),6.62–6.29 (m,1H),3.64(dtt,J=17.8,6.0,3.1Hz,3H),3.53(dd,J=13.1,3.9Hz,2H),3.06–2.97(m,1H),1.12(d,J=6.3Hz,3H).

[0470] LCMS(ESI):[M+H] + =258.20.

[0471] Step 6: Synthesis of compound ER-P-19-10

[0472] At room temperature, compound ER-P-19-8 (9 g, 34.98 mmol, 1.0 eq.) and Toluene / TFA (10 / 1, 99 mL) were added to a 250 mL single-necked flask, followed by ER-P-19-9 (13.01 g, 69.97 mmol, 2.0 eq.). The mixture was heated to 115 °C and reacted overnight. The system was then cooled and concentrated directly to dryness.

[0473] The sample was mixed with silica gel and purified by passing it through a normal phase column to obtain a yellow solid ER-P-19-10 (4.5 g, 30.25%).

[0474] 1 H NMR(400MHz,DMSO-d6)δ12.46(s,1H),8.59(d,J=2.4Hz,1H),8.06–7.91(m,1 H),7.41(d,J=8.5Hz,1H),7.19(dd,J=8.8,2.4Hz,1H),6.92(d,J=8.8Hz,1H) ,6.25–5.88(m,1H),5.10(s,1H),3.16(ddd,J=17.0,11.1,4.5Hz,3H),2.92( dd,J=17.3,8.0Hz,1H),2.66(dd,J=15.4,4.1Hz,1H),1.09(d,J=6.6Hz,3H).

[0475] LCMS(ESI):[M+H] + =460.20.

[0476] Step 7: Synthesis of compound ER-P-19-11

[0477] At room temperature, compounds ER-P-19-10 (2.38 g, 5.6 mmol, 1.0 eq.), compound 16 (2.88 g, 11.19 mmol, 2.0 eq.), Pd2(dba)3 (512 mg, 0.56 mmol, 0.1 eq.), RuPhos (522 mg, 1.12 mmol, 0.2 eq.), t-BuONa (1.61 g, 16.79 mmol, 3 eq.), and dioxane (35.7 mL) were added to a 250 mL single-necked flask, and the system was heated to 110 °C and reacted for 2 hours. The system was then cooled and concentrated directly to dryness, and purified by normal-phase column chromatography to obtain a yellow solid ER-P-19-11 (2.1 g, 62.36%).

[0478] 1H NMR (400MHz, DMSO-d6) δ12.40(s,1H),8.14(d,J=3.0Hz,1H),7.29(tt,J=6.3,2.7Hz,2H),7.15–7.09(m,1 H),6.85(d,J=8.8Hz,1H),6.10–5.63(m,2H),4.94(s,1H),4.03(dd,J=7.3,2.8Hz,1H),3.65(s,1H),3.54– 3.48(m,2H),3.23(d,J=1.1Hz,6H),3.18–3.02(m,2H),2.90(dt,J=23.5,8.9Hz,3H),2.70–2.57(m,2H),1 .85(d,J=12.0Hz,2H),1.71(d,J=9.9Hz,3H),1.57–1.47(m,3H),1.40–1.32(m,5H),1.06(d,J=6.6Hz,3H).

[0479] LCMS(ESI):[M+H] + =637.58.

[0480] Step 8: Synthesis of compound ER-P-19

[0481] Compound ER-P-19-11 (540 mg, 0.85 mmol, 1.1 eq.) was dissolved in formic acid (5 mL). The reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was dissolved in DMSO (2 mL). Compound 9 (300 mg, 0.77 mmol, 1.0 eq.) and sodium triacetoxyborohydride (489 mg, 2.31 mmol, 3.0 eq.) were added to the system. The reaction was carried out at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, and the crude product was purified by reverse column chromatography. The crude product was then subjected to Prep-HPLC to obtain a white solid compound ER-P-19 (300 mg, 44.46%).

[0482] 1H NMR (400MHz, DMSO-d6) δ12.46–12.40(m,1H),10.99(s,1H),7.36(d,J=7.6Hz,1H),7.27(d,J=7.6Hz,1H),7.16(dd, J=8.8,2.5Hz,1H),6.81(d,J=8.8Hz,1H),6.55(d,J=13.6Hz,2H),5.99–5.67(m,2H),5.21–5.08(m,2H),4.72–4.62( m,2H),4.40(d,J=17.2Hz,1H),4.24(d,J=17.2Hz,1H),3.45(d,J=6.0Hz,1H),3.11–2.84(m,9H),2.76–2.54(m,3H), 2.42(td,J=13.1,4.7Hz,2H),2.22(t,J=13.8Hz,2H),2.05–1.70(m,9H),1.63–1.18(m,11H),1.07(d,J=6.5Hz,3H).

[0483] Preparation of ER-P-3

[0484] Step 1: Synthesis of compound ER-P-3-2

[0485] Compound ER-P-3-1 (2.5 g, 11.63 mmol, 1.0 eq) was dissolved in tetrahydrofuran (13 mL). n-BuMgCl (9 mL, 17.45 mmol, 1.5 eq) and n-BuLi (22 mL, 34.89 mmol, 3.0 eq) were added to the reaction system at 0 °C, and the reaction was carried out for 2 hours. ER-P-19-4 (3.86 g, 16.28 mmol, 1.4 eq) was added to the reaction system, and the reaction was carried out for 2 hours. The reaction system was quenched with saturated ammonium chloride aqueous solution, the pH was adjusted to 5-6 with 2 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain a pale yellow solid compound ER-P-3-2 (2.4 g, 70.37%).

[0486] 1 H NMR (600MHz, DMSO-d6) δ13.54(s,1H),8.28(s,1H),7.10–7.04(m,1H),6.82(d,J=7.9Hz,2H),3.77(dq,J=13. 4,6.7Hz,1H),3.01(dd,J=13.2,6.7Hz,1H),2.82(dd,J=13.2,6.8Hz,1H),1.31(s,9H),1.03(d,J=6.6Hz,3H).

[0487] LCMS(ESI):[M+H] + =294.35.

[0488] Step 2: Synthesis of compound ER-P-3-3

[0489] Compound ER-P-3-2 (2.4 g, 8.18 mmol, 1.0 eq) was dissolved in dichloromethane (15 mL), cooled to 0 °C, and then a dioxane solution of hydrochloric acid (15 mL) was added. After the addition was complete, the mixture was allowed to return to room temperature and reacted for 2 hours. The reaction solution was concentrated under reduced pressure. The crude product ER-P-3-3 (2.3 g) obtained from the concentrated organic phase was used directly in the next reaction step.

[0490] 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),8.46(d,J=3.5Hz,1H),8.39(s,2H),7.11(dd,J=11.2,7.7H z,1H),6.91(dd,J=7.7,4.0Hz,1H),3.51–3.36(m,2H),3.01–2.91(m,1H),1.14(d,J=6.4Hz,3H).

[0491] LCMS(ESI):[M+H] + =194.24.

[0492] Step 3: Synthesis of compound ER-P-3-4

[0493] Compounds ER-P-3-3 (2.3 g, 11.9 mmol, 1.0 eq), ER-P-19-7 (3.1 g, 14.28 mmol, 1.2 eq), and DIEA (6.4 mL, 47.6 mmol, 4 eq) were dissolved in dioxane (25 mL) and reacted at 80 °C for 2 hours under nitrogen protection. After cooling the reaction system to room temperature, it was concentrated under reduced pressure and purified by column chromatography to give a yellow solid compound ER-P-3-4 (1.8 g, 58.82%).

[0494] 1 H NMR (400MHz, DMSO-d6) δ13.58(s,1H),8.29–8.19(m,1H),7.07(dd,J=11.2,7.7Hz,1H),6.84(dd,J=7.7,4.1Hz ,1H),6.10–5.77(m,1H),3.13–2.87(m,4H),2.71(dd,J=12.9,7.6Hz,1H),1.87(s,1H),0.91(d,J=6.2Hz,3H).

[0495] LCMS(ESI):[M+H] + =258.16.

[0496] Step 4: Synthesis of compound ER-P-3-5

[0497] Compound ER-P-3-4 (1.8 g, 7.00 mmol, 1.0 eq) was dissolved in toluene (15 mL), and trifluoroacetic acid (2 mL) and ER-P-19-9 (4.6 g, 20.99 mmol, 3.0 eq) were added dropwise to the system. The reaction was carried out at 115 °C for 24 hours. After cooling the reaction system to room temperature, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentrating the organic phase was purified by column chromatography to give a yellow oily compound ER-P-3-5 (1.67 g, 51.86%).

[0498] 1 H NMR (400MHz, DMSO-d6) δ13.62(s,1H),8.27–8.13(m,1H),7.39(d,J=8.8Hz,2H),6.63(d,J=11.6Hz,1H),6.11–5.73(m,1H),5.28(s,1 H),3.41(p,J=6.0Hz,1H),3.17–3.04(m,2H),2.89(dd,J=16.6,6.0Hz,1H),2.60(qd,J=16.4,15.5,4.0Hz,1H),1.05(d,J=6.5Hz,3H).

[0499] LCMS(ESI)[M+H] + =460.29.

[0500] Step 5: Synthesis of compound ER-P-3-6

[0501] Compound ER-P-3-5 (1.67 g, 3.63 mmol, 1.0 eq) was dissolved in dioxane (20 mL), and compound 16 (1.87 g, 7.26 mmol, 2 eq), Pd2(dba)3 (332 mg, 0.36 mmol, 0.1 eq), Ruphos (339 mg, 0.73 mmol, 0.2 eq), and sodium tert-butoxide (1.05 g, 10.89 mmol, 3.0 eq) were added. The system was reacted at 110 °C for 2 hours. After cooling the reaction system to room temperature, it was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography to give a yellow oily compound ER-P-3-6 (1.2 g, 51.94%).

[0502] 1 H NMR (400MHz, DMSO-d6) δ13.58(s,1H),8.24–8.10(m,1H),6.58–6.53(m,2H),6.52(s,1H),5. 99–5.69(m,1H),5.15(s,1H),4.03(d,J=7.2Hz,1H),3.64(s,1H),3.55–3.48(m,3H),3.43(dt ,J=11.0,5.5Hz,1H),3.23(s,6H),3.14–2.94(m,4H),2.85(dd,J=16.5,5.9Hz,1H),2.64(dd, J=12.1,3.3Hz,1H),1.75(dd,J=39.3,10.1Hz,4H),1.50–1.29(m,9H),1.06(d,J=6.5Hz,3H).

[0503] LCMS(ESI)[M+H] + =637.45.

[0504] Step 6: Synthesis of compound ER-P-3

[0505] Compound ER-P-3-6 (1.2 g, 1.88 mmol, 1.0 eq) was dissolved in formic acid (15 mL). The reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was used directly in the next step. The crude product (100 mg, 0.26 mmol, 1.0 eq) was dissolved in DMSO (2 mL), and compound 9 (182 mg, 0.31 mmol, 1.2 eq) and sodium triacetoxyborohydride (82 mg, 0.38 mmol, 1.5 eq) were added to the system. The reaction was carried out at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, and the crude product was purified by reverse column chromatography. The crude product was then subjected to Prep-HPLC to obtain a white solid compound ER-P-3 (90 mg, 36.38%).

[0506] 1H NMR (400MHz, DMSO-d6) δ13.57(s,1H),10.99(s,1H),8.20(d,J=3.4Hz,1H),7.41–7.22(m,2H),6.55(dd, J=12.5,4.6Hz,3H),5.85(tt,J=56.3,4.3Hz,1H),5.19–5.03(m,2H),4.70–4.55(m,2H),4.40(d,J=17.2H z,1H),4.24(d,J=17.2Hz,1H),3.50–3.35(m,4H),3.17–2.81(m,11H),2.70–2.55(m,2H),2.43(dd,J=13. 2,4.7Hz,1H),2.22(td,J=14.7,4.2Hz,2H),2.08–1.66(m,9H),1.63–1.29(m,9H),1.07(d,J=6.5Hz,3H).

[0507] LC-MS(ESI):[M+H] + =930.85.

[0508] Synthetic routes of intermediate compounds

[0509] Preparation of intermediate compound 9

[0510] Step 1: Synthesis of Compound 2

[0511] Compound 1 (110 g, 206.87 mmol, 1.0 eq) was dissolved in methanol (500 mL), and sulfuric acid (55 mL) was added to the reaction system at 0 °C. The reaction was carried out at 65 °C for 3 hours. The mixture was concentrated under reduced pressure, and the crude product obtained after concentration was washed with water and filtered to give compound 2 (95 g, 81.12%) as a white solid.

[0512] 1 H NMR (600MHz, DMSO-d6) δ10.74(s,1H),7.64(d,J=8.2Hz,1H),7.53(d,J=2.0Hz,1H),7.31(d,J=8.3,2.0Hz,1H),3.84(s,3H).

[0513] LCMS(ESI):[M+H] + =228.89.

[0514] Step 2: Synthesis of Compound 3

[0515] Compound 2 (60 g, 259.69 mmol, 1.0 eq) was dissolved in trifluoroacetic acid (500 mL), and hexamethylenetetramine (121.35 g, 865.63 mmol, 4.0 eq) was added. After the addition was complete, the mixture was heated to 125 °C and reacted for 16 hours. The reaction system was cooled to room temperature, quenched with 2 M hydrochloric acid, and filtered to give a yellow solid, compound 3 (27 g, 40.13%).

[0516] 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),8.01(d,J=8.2Hz,1H),7.31(d,J=8.2Hz,1H),3.88(s,3H).

[0517] LCMS(ESI):[M+H] + =257.07.

[0518] Step 3: Synthesis of Compound 5

[0519] Compound 3 (25 g, 96.50 mmol, 1.0 eq), compound 4 (24.19 g, 101.33 mmol, 1.05 eq), sodium cyanoborohydride (12.13 g, 193.01 mmol, 2.0 eq), acetic acid (8.3 mL, 144.76 mmol, 1.5 eq), and DIEA (17.7 mL, 101.33 mmol, 1.05 eq) were dissolved in methanol (450 mL) at -20 °C, and the reaction was carried out at 20 °C for 3 hours under nitrogen protection. The reaction mixture was quenched with water and extracted with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentrating the organic phase was purified by column chromatography to give compound 5 (30 g, 75.22%), a yellow oil.

[0520] 1 H NMR(600MHz,Chloroform-d)δ7.61(d,J=8.0Hz,1H),7.33(d,J=8.0Hz,1H),6.40(s,1H),5.46(s,1H),4.92(dd,J=8 .9,6.3Hz,1H),4.59(d,J=17.6Hz,1H),4.48(d,J=17.6Hz,1H),2.45–2.24(m,3H),2.22–2.14(m,1H),1.45(s,9H).

[0521] LCMS(ESI):[M+H-Boc] + =312.08.

[0522] Step 4: Synthesis of Compound 7

[0523] Compound 5 (15 g, 44.23 mmol, 1.0 eq) and compound 6 (10.38 g, 48.65 mmol, 1.1 eq) were dissolved in tetrahydrofuran (150 mL). Triphenylphosphine (23.0 g, 88.46 mmol, 2.00 eq) and diethyl azodicarbonate (15.41 g, 88.46 mmol, 2.0 eq) were added to the system at 0 °C. The system was then heated to room temperature and reacted for 8 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentrating the organic phase was purified by column chromatography to give compound 7 (20 g, 54.62%) as a yellow oil.

[0524] 1 H NMR(600MHz,Chloroform-d)δ7.71–7.67(m,1H),7.45(dd,J=8.0,1.1Hz,1H),6 .42–6.38(m,1H),5.87(s,1H),5.55(s,1H),4.92(dd,J=8.6,6.3Hz,1H),4.65( d,J=17.3Hz,1H),4.56–4.49(m,3H),3.99(s,2H),3.61(s,2H),2.42–2.25(m,5 H), 2.17(dt,J=12.5,8.1Hz,1H), 1.50(d,J=1.1Hz,9H), 1.43(d,J=1.1Hz,9H).

[0525] LCMS(ESI)[M+H-Boc] + =508.29.

[0526] Step 5: Synthesis of Compound 8

[0527] Compound 7 (30 g, 72.41 mmol, 1.0 eq) was dissolved in toluene (120 mL), and azobisisobutyronitrile (3.57 g, 21.72 mmol, 0.3 eq) and tributyltin (105.38 g, 362.06 mmol, 5.0 eq) were added. The system was reacted at 110 °C for 16 h. After cooling to room temperature, the reaction system was quenched with a saturated cesium fluoride aqueous solution and extracted with ethyl acetate. The mixture was washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate. The crude product obtained by concentrating the organic phase was purified by column chromatography to give compound 8 (16 g, 70.05%) as a white solid.

[0528] 1H NMR(600MHz,Chloroform-d)δ7.45(d,J=7.6Hz,1H),7.24(d,J=7.6Hz,1H),6.29(s,1H),5.32(s,1H),4.90(dd,J=9.0,6.4Hz,1H),4.55(s,2H), 4.49(d,J=17.0Hz,1H),4.41(d,J=17.1Hz,1H),2.90(s,2H),2.45–2.13 (m,6H),1.90(s,2H),1.76(d,J=13.5Hz,2H),1.51(s,9H),1.44(s,9H).

[0529] LCMS(ESI)[M+H-tBu] + =474.39.

[0530] Step 6: Synthesis of Compound 9

[0531] Compound benzenesulfonic acid (14.93 g, 94.40 mmol, 2.0 eq) was dissolved in acetonitrile (100 mL) and heated to 100 °C. Compound 8 (25 g, 47.20 mmol, 1.0 eq) was then added to the system. The reaction was carried out at 80 °C for 12 hours. After cooling the reaction system to room temperature, it was filtered to give a white solid compound 9 (13 g, 53.63%).

[0532] 1 H NMR (600MHz, DMSO-d6) δ11.00(s,1H),7.35(d,J=7.6Hz,1H),7.30(d,J=7.6Hz,1H),5.10(dd,J=13. 3,5.1Hz,1H),4.70–4.63(m,2H),4.40(d,J=17.1Hz,1H),4.24(d,J=17.1Hz,1H),3.38–3.30(m,2H), 3.01(q,J=12.3Hz,2H),2.92(ddd,J=17.3,13.7,5.4Hz,1H),2.66–2.58(m,1H),2.43(qd,J=13.3,4 .5Hz,1H),2.15(td,J=13.7,4.2Hz,2H),1.98(dtd,J=12.8,5.4,2.3Hz,1H),1.89(d,J=16.3Hz,2H).

[0533] LCMS(ESI)[M+H] + =356.35.

[0534] Preparation of intermediate compound 19

[0535] Step 1: Synthesis of Compound 14

[0536] Compound 13 (50 g) and imidazole (51.6 g) were dissolved in DMF (500 ml) at room temperature. The system was cooled to 0 °C, and then trimethylchlorosilane (41.2 g) was added dropwise. After the addition was complete, the system was heated to room temperature and stirred overnight. TLC analysis was performed. After the reaction was complete, the compound was dissolved in ethyl acetate, washed three times with water, and the aqueous phase was extracted three times with ethyl acetate. The ethyl acetate was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography. The mobile phase EA / PA = 20% yielded a peak. The collected solution was concentrated to give compound 14 (59 g, 97%) as a colorless oil.

[0537] 1 H NMR (400MHz, DMSO-d6) δ3.85(p,J=4.2Hz,1H),3.58(s,3H),2.42–2.29(m,1H),1.87-1.73(m,2H),1.60–1.45(m,6H).

[0538] LCMS(ESI)[M+H] + =No signal

[0539] Step 2: Synthesis of Compound 15

[0540] Compound 14 (11 g) and 1-Cbz-piperidin-4-one (9.9 g) were dissolved in ultra-dry dichloromethane. The air was purged three times with nitrogen. Under nitrogen protection, the system was cooled to -78 °C, and then trimethylsilyltrifluoromethane sulfonate (1.1 g) was slowly added dropwise. After the addition was complete, the reaction was stirred at -78 °C for 1 hour. Then, a dichloromethane solution (10 ml) of triethylsilane (5.8 g) was slowly added dropwise. After the addition was complete, the system was moved to room temperature and stirred overnight. TLC analysis was performed. After the reaction was complete, the reaction solution was concentrated, stirred, and purified by column chromatography. The mobile phase EA / PE ratio was 30%, and the peak was obtained by concentrating and collecting the solution to give a yellow oily compound 15 (13.7 g, 73%).

[0541] 1 H NMR (400MHz, DMSO-d6) δ7.40–7.25(m,5H),5.07(s,2H),3.75-3.65(m,2H),3.61–3.47(m,5H),3.13(s,2H),2.42–2.32(m,2H),1.83–1.28(m,12H).

[0542] LCMS(ESI)[M+H] + =376.40

[0543] Step 3: Synthesis of Compound 16

[0544] Compound 15 (6.8 g) was dissolved in tetrahydrofuran (10 ml) at room temperature. The system was purged with nitrogen three times. Lithium aluminum hydride (0.82 g) was slowly added under ice bath conditions, and the reaction was carried out under ice bath conditions for 3 h. The reaction was detected by TLC. After the reaction was completed, water was added dropwise under ice bath conditions to quench the reaction. The mixture was filtered, the filtrate was evaporated to dryness and stirred, and purified by column chromatography. The mobile phase EA / PE ratio was 47%, and the peak was obtained. The collected solution was concentrated to give a colorless oily compound 16 (4.5 g, 71%).

[0545] 1 H NMR(600MHz, DMSO-d6)δ7.41–7.30(m,5H),5.07(s,2H),4.36(t,J=5.3Hz,1H),3.73–3.66(m,2H),3.64–3.60(m,1H), 3.55–3.50(m,1H),3.22(t,J=5.8Hz,2H),3.18–3.06(m,2H),1.77–1.71(m,2H),1.70-1.63(m,2H),1.47–1.20(m,9H).

[0546] LCMS(ESI)[M+H] + =348.35

[0547] Step 4: Synthesis of Compound 17

[0548] Oxaloyl chloride (3.3 g) was dissolved in dichloromethane (300 ml), nitrogen was purged three times, and the temperature was lowered to -80°C. Then, a dichloromethane solution (10 ml) of DMSO (2.7 g) was slowly added dropwise. After the addition was complete, the mixture was stirred at this temperature for 15 minutes. Then, a dichloromethane solution (10 ml) of compound 16 (6 g) was slowly added dropwise, and the mixture was stirred at -80°C for 20 minutes. Then, a dichloromethane solution (5 ml) of triethylamine (7.0 g) was slowly added dropwise. After the addition was complete, the reaction system was slowly heated to room temperature and stirred at room temperature for 20 minutes. Finally, water (5 ml) was added dropwise to quench the system. The reaction system was washed three times with water. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography. The mobile phase EA / PE ratio was 30%, and the peak was eluted. The collected liquid was evaporated to dryness to obtain anhydrous oily compound 17 (4 g, 67%).

[0549] 1H NMR(600MHz,DMSO-d6)δ9.57(s,1H),7.40–7.30(m,5H),5.06(s,2H),3.73-3.63(m,2H),3.59–3.51(m,2H),3.2 0-3.05(m,2H),2.37-2.31(m,1H),1.77–1.67(m,4H),1.62-1.53(m,4H),1.53–1.45(m,2H),1.36–1.28(m,2H).

[0550] LCMS(ESI)[M+H] + =346.39

[0551] Step 5: Synthesis of Compound 18

[0552] Compound 17 (1.6 g) was dissolved in methanol (7 ml) at room temperature, followed by the addition of p-toluenesulfonic acid (80 mg) and trimethyl orthoformate (4.9 g). The mixture was heated to 35 °C and stirred for 3 h. After the reaction was completed by TLC, the mixture was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution until pH = 8. The ethyl acetate was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography. The mobile phase showed a peak at EA / PE = 10%. The collected solution was evaporated to dryness to give compound 17 (1.4 g, 78%) as a colorless oil.

[0553] 1 H NMR (600MHz, DMSO-d6) δ7.45–7.27(m,5H),5.07(s,2H),4.04(d,J=7.2,1H),3.73–3.66(m,2H),3.65–3.61(m,1 H),3.55–3.49(m,1H),3.23(s,6H),3.19–3.05(m,2H),1.78–1.67(m,4H),1.61-1.53(m,1H),1.45–1.27(m,8H).

[0554] Step 6: Synthesis of Compound 19

[0555] Compound 18 (1.1 g) was dissolved in methanol (6 ml) at room temperature, and palladium on carbon (220 mg, 55% in water) was added. The system was purged with hydrogen three times and reacted under hydrogen atmosphere for 12 hours. After the reaction was completed by TLC, palladium on carbon was filtered, and the filtrate was concentrated to obtain a colorless oily compound 19 (0.7 g, 96%).

[0556] 1H NMR(400MHz,DMSO-d6)δ4.03(d,J=7.2Hz,1H),3.64–3.54(m,1H),3.45–3.28(m,2H),3.23(s,6H) ,2.98–2.83(m,2H),2.56–2.41(m,2H),1.80–1.62(m,4H),1.61–1.49(m,1H),1.48–1.18(m,8H).

[0557] LCMS(ESI)[M+H] + =258.47

[0558] The compounds listed in Table A below were synthesized based on the above general formula and examples.

[0559] Table A:

[0560] PROTAC Synthesis Formula ER-T-1

[0561] PROTAC Synthesis Formula ER-T-3

[0562] PROTAC Synthesis Formula ER-T-4

[0563] PROTAC Synthesis General Formula ER-T-5

[0564] PROTAC Synthesis Formula ER-T-6

[0565] PROTAC Synthesis Formula ER-T-7

[0566] PROTAC Synthesis Formula ER-T-8

[0567] PROTAC Synthesis Formula ER-T-9

[0568] PROTAC Synthesis General Formula ER-T-10

[0569] PROTAC Synthesis Formula ER-T-11

[0570] PROTAC Synthesis General Formula ER-T-12

[0571] PROTAC Synthesis General Formula ER-T-13

[0572] PROTAC Synthesis Formula ER-T-14

[0573] PROTAC Synthesis General Formula ER-T-15

[0574] PROTAC Synthesis Formula ER-T-16

[0575] PROTAC Synthesis Formula ER-T-17

[0576] The compounds listed in Table B below were synthesized based on the above general formula and examples.

[0577] Table B:

[0578] Example 1: Inhibitory effect on cell proliferation in T-47D cells

[0579] The complete culture medium required for T-47D (ATCC) cells was RPMI 1640 (ATCC, Product number: 30-2001) medium containing 10% fetal bovine serum and 0.0069 mg / mL insulin. T-47D cells were seeded at a density of 3,000 cells / well in 96-well plates. Simultaneously, final concentrations of 10.00, 1.00, 0.10, 0.01, 0.001, 0.0001, 0.00001, 0.000001, and 0.0000001 μM of the PROTAC compound provided in this embodiment and the positive control ARV-471 (source: Inokai) were prepared to treat the cells, and the cells were incubated at 37°C in a 5% CO2 cell incubator for 6 days. Cell viability was assessed using a CCK-8 assay kit (Beyotime, Product number: C0040) according to the manufacturer's instructions. The IC50 of each compound after 6 days of treatment was calculated using GraphPadPrism software based on the inhibition rate. 50 The values ​​are shown in Table 1.

[0580] The structure of the ARV-471 is as follows:

[0581] Table 1. Inhibition IC50 of the PROTAC compound and positive control sample provided in this invention on T-47D cell proliferation 50 value

[0582] Conclusion: The PROTAC compounds provided in this invention can effectively inhibit the proliferation of T-47D cells. The inhibitory effects of some compounds are comparable to or even better than those of the positive control.

[0583] Example 2: Inhibitory effect on cell proliferation in MCF-7 cells

[0584] The complete culture medium required for MCF-7 cells (derived from ATCC) was DMEM (gibco, Product number: 11995-065) basal medium containing 10% fetal bovine serum. MCF-7 cells were seeded at a density of 800 cells / well in 96-well plates. Simultaneously, final concentrations of 100.00, 20.00, 4.00, 0.80, 0.16, 0.032, 0.0064, 0.0013, and 0.00027 μM of the PROTAC compound provided in this embodiment and the positive control ARV-471 (derived from Innoca) were prepared to treat the cells, and the cells were incubated at 37°C in a 5% CO2 cell culture incubator for 9 days. Cell viability was assessed using a CCK-8 assay kit (Beyotime, Product number: C0040) according to the manufacturer's instructions. The IC50 of each PROTAC compound after 9 days of treatment was calculated using GraphPadPrism software based on the inhibition rate. 50 The values ​​are shown in Table 2.

[0585] Table 2. Inhibition IC50 of the PROTAC compound and positive control of the present invention on MCF-7 cell proliferation 50 value

[0586] Conclusion: The PROTAC compounds of the present invention can effectively inhibit the proliferation of MCF-7 cells, and the inhibitory effect of some PROTAC compounds on MCF-7 cells is comparable to or even better than that of the positive control.

[0587] Experimental Example 3: Degradation of ERα in MCF-7 cells

[0588] MCF-7 (ATCC) cells were cultured in DMEM medium (11995-065, Gibco) containing 10% FBS (10099141C, Gibco) at 37°C and 5% CO2 until they entered the logarithmic growth phase. MCF-7 cells were then cultured at a rate of 3 × 10⁻⁶ cells / year. 5 Cells were seeded at a density of cells / well in 6-well plates and cultured at 37°C with 5% CO2 for 24 h. After cell attachment, 1 μL of dimethyl sulfoxide solution (final concentration 0.15–1000 nM) was added, and the cells were incubated at 37°C with 5% CO2 for another 4 h. After 4 h, the culture medium was discarded, and each well was washed once with 1 mL of pre-chilled 1×DPBS. Cells were then lysed with 50 μL of RIPA lysis buffer (P0013B, Beyotime) and a 1× protease inhibitor mixture (P1005, Beyotime). After standing on ice for 20 min, the cells were centrifuged at 14000g at 4°C for 30 min. The supernatant was carefully collected and the protein level of ERα was detected by Western blotting.

[0589] Western blotting: The total protein concentration in the collected cell lysis supernatant was determined using a BCA protein concentration assay kit (enhanced version) (P0009, Beyotime). Based on the total protein concentration detected by BCA, the concentration was adjusted to 1 μg / μL with RIPA lysis buffer and 5×SDS-PAGE protein loading buffer (MB01015, GenScript). The protein was denatured at 95°C for 5 min. After denaturation, the condensate on the centrifuge tube wall was collected as the loading sample. 20 μL of the loading sample (20 μg total protein) was added to the wells of a 12% precast gel (M00669, GenScript). Electrophoresis was performed at 100V for 20 min, followed by electrophoresis at 150V for 40 min. After electrophoresis, the protein from the SDS-PAGE gel was transferred to a PVDF membrane and transferred at a constant voltage of 100V for 60 min. After transfer, PVDF membranes corresponding to the ERα protein and internal control protein were cut and incubated in 1×QμickBlock blocking buffer (P0252, Beyotime) at room temperature with shaking for 30 min. After blocking, ERα primary antibody (1:1000, 8644S, CST) was added and incubated overnight at 4℃ with shaking. After incubation, the PVDF membranes were washed three times with 1×TBST buffer for 5 min each time; Rabbit IgG (H+L) secondary antibody (1:7500, SA5-35571, Invitrogen) was added and incubated at room temperature with shaking for 1 h, followed by washing three times with 1×TBST buffer for 5 min each time; finally, scanning and imaging were performed using a dual-color infrared laser imaging system (Odyssey DLx, LI-COR). The protein maps were analyzed for grayscale values ​​using Image Studio Lite software. The grayscale correction value for each sample was calculated using the formula: Grayscale correction value = Target protein grayscale value / Corresponding internal control grayscale value. The degradation rate of the compounds was then calculated by comparing the grayscale correction values ​​of the compound group and the DMSO group.

[0590] Table 3. Degradation rate (%) of ERα in MCF-7 cells by the PROTAC compound of the present invention and the positive control.

[0591] Conclusion: Compared with the positive control, the PROTAC compound of the present invention has a significant degradation effect on ERα in MCF-7 cells at concentrations of 10 nm and 1 nM.

[0592] Experimental Example 4: Degradation of ERα in T-47D cells

[0593] T-47D (ATCC) cells were cultured in RPMI 1640 (ATCC, 30-2001) medium containing 10% FBS (10099141C, Gibco) and 0.0069 mg / mL insulin at 37°C and 5% CO2 until they entered the logarithmic growth phase. T-47D cells were then cultured at a rate of 3 × 10⁻⁶ cells / year. 5 Cells were seeded at a density of cells / well in 6-well plates and cultured at 37°C with 5% CO2 for 24 h. After cell attachment, 1 μL of dimethyl sulfoxide solution (final concentration 0.15–1000 nM) was added, and the cells were incubated at 37°C with 5% CO2 for another 4 h. After 4 h, the culture medium was discarded, and each well was washed once with 1 mL of pre-chilled 1×DPBS. Cells were then lysed with 50 μL of RIPA lysis buffer (P0013B, Beyotime) and a 1× protease inhibitor mixture (P1005, Beyotime). After standing on ice for 20 min, the cells were centrifuged at 14000g at 4°C for 30 min. The supernatant was carefully collected and the protein level of ERα was detected by Western blotting.

[0594] Table 4-1 Degradation rate (%) of ERα by the PROTAC compound and positive control sample of the present invention in T-47D cells Note: "-" indicates no test results.

[0595] Conclusion: Compared with the positive control, the PROTAC compound of the present invention has a significant degradation effect on ERα in T-47D cells at concentrations of 10 nM and 1 nM.

[0596] Table 4-2 Degradation rate (%) of the PROTAC compound of the present invention on ERα in T-47D cells

[0597] Note: "-" indicates no test results.

[0598] The PROTAC compound disclosed herein exhibits significant degradation activity against ERα in T-47D cells at concentrations of 1000 nM and 100 nM.

[0599] 2. The degradation of IKZF2 in T-47D cells by the PROTAC compound of the present invention.

[0600] T-47D (HTB-133, ATCC) cells were cultured in RPMI 1640 medium (30-2001, ATCC) containing 10% FBS (SH30406.05, Hyclone) at 37°C and 5% CO2 until they entered the logarithmic growth phase. 2 mL of T-47D cells were seeded into each well of a 6-well cell culture plate, at a cell density of 2 × 10⁶ cells / well. 5 Cells were cultured per well with 1 μL of a compound solution diluted with dimethyl sulfoxide (final concentration 0.15–1000 nM) at 37°C and 5% CO2 for 24 hours. The culture medium was then discarded, and the cells were washed twice with PBS. 40 μL of RIPA lysis buffer (P0013B, Beyotime) and a 1× protease inhibitor mixture (P1005, Beyotime) were added to each well to resuspend the lysed cells. After standing on ice for 15 min, the lysed cell mixture was collected in a 1.5 mL centrifuge tube and centrifuged at 12000 rpm and 4°C for 30 min. The supernatant was carefully collected and the IKZF2 protein level was detected by Western blotting.

[0601] Table 4-3 Degradation of IKZF2 in T-47D cells by the PROTAC compound of the present invention and positive control 50

[0602] Table 4-4 Degradation rate (%) of the PROTAC compound of the present invention for IKZF2 in T-47D cells Note: "-" indicates no test results.

[0603] Conclusion: The PROTAC compound of this invention has a significant degradation effect on IKZF2 in T-47D cells.

[0604] The structure of the control compound used in the experimental example is as follows:

[0605] Experiment Example 5: Anti-tumor cell proliferation experiment

[0606] Experimental methods and principles:

[0607] MCF-7 WT Cells (ATCC, HTB-22) were cultured in DMEM (Gibco, 11995-065) complete medium containing 10% fetal bovine serum (Hyclone, SH30406.05). T-47D WT Cells (ATCC, HTB-133) were cultured in RPMI 1640 (ATCC, 30-2001) complete medium containing 10% fetal bovine serum (Hyclone, SH30406.05) and 0.0069 mg / mL insulin. ZR-75-1WT Cells (ATCC, CRL-1500) were cultured in RPMI 1640 (ATCC, 30-2001) complete medium containing 10% fetal bovine serum (Hyclone, SH30406.05). MCF-7 Y537S MCF-7 D538G T-47D D538G It is a monoclonal cell line obtained using ATCC's MCF-7 and T-47D cells via CRISPR-Cas9 technology, and the culture method is the same as that of the WT type.

[0608] 1. T-47D D538G Cells: Cells were seeded at a density of 3,000 cells per well in 96-well plates using RPMI 1640 containing fetal bovine serum and 0.0069 mg / mL insulin, and incubated at 37°C in a 5% CO2 cell culture incubator for 24 h. Cells were then treated with PROTAC compound at final concentrations of 10.00, 1.00, 0.10, 0.01, 0.001, 0.0001, 0.00001, 0.000001, and 0.0000001 μM, as well as the positive control ARV-471, and incubated at 37°C in a 5% CO2 cell culture incubator for 6 days. Cell viability was assessed using a CCK-8 assay kit (Beyotime, Product number: C0040) according to the manufacturer's instructions. The IC50 of each compound after 6 days of treatment was calculated using GraphPadPrism software based on the inhibition rate. 50 value.

[0609] 2. T-47D WT Cells: Cells were seeded at a density of 3,000 cells per well in 96-well plates using RPMI 1640 complete medium containing 10% fetal bovine serum and 0.0069 mg / mL insulin, and cultured at 37°C in a 5% CO2 incubator for 24 h. Cells were then treated with PROTAC compound at final concentrations of 10.00, 1.00, 0.10, 0.01, 0.001, 0.0001, 0.00001, 0.000001, and 0.0000001 μM, as well as the positive control ARV-471, and incubated at 37°C in a 5% CO2 incubator for 6 days. Cell viability was assessed using a CCK-8 assay kit (Beyotime, Product number: C0040) according to the manufacturer's instructions. The IC50 of each compound after 6 days of treatment was calculated using GraphPadPrism software based on the inhibition rate. 50 value.

[0610] 3. MCF-7 WT Cells, MCF-7 Y537S and MCF-7 D538GCells: Cells were seeded at a density of 2000 cells per well in 96-well plates using DMEM (Gibco, 11995-065) containing 10% fetal bovine serum and cultured at 37°C in a 5% CO2 incubator for 24 h to allow cell adhesion. PROTAC compounds and the positive control ARV-471 were prepared at final concentrations of 100.00, 50.00, 25.00, 12.50, 6.25, 3.13, 1.56, 0.78, and 0.39 μM and incubated for 5 days at 37°C in a 5% CO2 incubator. Cell viability was assessed using a CCK-8 assay kit (Beyotime, Product number: C0040) according to the manufacturer's instructions. The IC50 of each PROTAC compound after 5 days of treatment was calculated using GraphPadPrism software based on the inhibition rate. 50 value.

[0611] 4.ZR-57-1 WT Cells: Cells were seeded at a density of 2000 cells per well in 96-well plates using RPMI 1640 containing 10% fetal bovine serum and incubated at 37°C in a 5% CO2 cell culture incubator for 24 h to allow cell adhesion. PROTAC compounds and positive control ARV-471 were prepared at final concentrations of 100.00, 50.00, 25.00, 12.50, 6.25, 3.13, 1.56, 0.78, and 0.39 μM and incubated for 5 days at 37°C in a 5% CO2 cell culture incubator. Cell viability was assessed using a CTG kit (Promega, Product number: G9242) according to the manufacturer's instructions. The IC50 of each PROTAC compound after 5 days of treatment was calculated using GraphPadPrism software based on the inhibition rate. 50 value.

[0612] Table 5 In vitro cell activity Note: " / " indicates no test results. max This represents the maximum inhibition rate that the compound can achieve within the tested concentration range.

[0613] The exemplary compounds of this invention exhibit strong inhibitory activity against different tumor cells.

[0614] Experiment 6: Degradation of target protein ERα

[0615] MCF-7 WT (ATCC, HTB-22), MCF-7 Y537S MCF-7 D538GCells were seeded at a density of 300,000 cells per well in 6-well plates using DMEM (Gibco, 11995-065) complete medium containing 10% fetal bovine serum (Hyclone, SH30406.05); T-47D WT (ATCC, HTB-133), T-47D D538G Cells were seeded in 6-well plates at a density of 200,000 cells per well using RPMI 1640 (ATCC, 30-2001) complete medium containing 10% fetal bovine serum (Hyclone, SH30406.05) and 0.0069 mg / mL insulin; ZR-57-1 WT (ATCC, CRL-1500) cells were seeded in 6-well plates at a density of 200,000 cells per well using RPMI 1640 (ATCC, 30-2001) complete medium containing 10% fetal bovine serum (Hyclone, SH30406.05). After 24 hours of incubation at 37°C, the cells adhered to the plates before drug administration. A 0.5‰ DMSO solution served as the blank control, ARV471 as the positive control, and the test compound as the drug administration group. 1 μL of DMSO was added to the blank control, while 1 μL of a 3-fold serially diluted positive control and test compound were added to the positive control and drug administration groups, respectively, resulting in a final concentration of 0–1000 nM. After 4 hours of culture, cell lysis samples were collected into 1.5 mL EP tubes, centrifuged at 12000 rpm for 15 minutes at 4°C, and then quantified and prepared using the BCA method. The cells were then heat-denatured in a metal bath at 95°C for 5 minutes. Protein samples were electrophoresed on a 12% precast gel. After the protein bands separated, they were transferred to a 0.45 μm PVDF membrane using a transfer device. The membrane was blocked with 5% skim milk powder for 1 h, and then primary antibodies (anti-ERα 1:1000 (CST cat#:8644s) and anti-ACTIN 1:1000 (CST cat#:4970s, Beyotime cat#:AF5003) were added. The membrane was incubated overnight at 4°C. The next day, the membrane was washed three times with TBST, and then the secondary fluorescent antibody (Goat anti-Rabbit 1:30000 (Thermo cat#:A32735)) was added. The membrane was incubated at room temperature for 1 h, and then washed three more times with TBST. Finally, the membrane was exposed using a gel imaging system (LI-COR, Odyssey CLx System). The bands were analyzed using ImageStudio, and the data were processed using GraphPadPrism 8.0 to calculate the concentration density (DC). 50 (nM).

[0616] Table 6 Degradation activity of wild-type ERα protein

[0617] Table 7 Degradation activity of mutant ERα protein Note: DC 50 (nM) represents the concentration of the compound that degrades 50% of the ERα protein; D max (%) represents the maximum degradation rate achievable by the compound within the tested concentration range; AUC degr Area under the blood drug concentration-time curve; D @1000nM (%) represents the degradation rate (%) when the compound concentration is 1000 nM.

[0618] Exemplary compounds of the present invention against MCF-7 WT T-47D WT ZR-57-1 WT MCF-7 Y537S MCF-7 D538G and T-47D D538G ERα proteins in cells all exhibit strong degradation activity.

[0619] Experiment 7: Degradation of target protein IKZF2

[0620] T-47D cells were cultured in RPMI 1640 (ATCC, 30-2001) complete medium containing 10% FBS (Hyclone, SH30406.05) and 0.0069 mg / mL insulin. Cells were seeded at a density of 200,000 cells per well in 6-well plates (2 mL volume). After 24 h of adhesion at 37°C, the cells were drugged. A 0.5‰ DMSO solution served as the blank control, NVP-DKY709 as the positive control, and the test compound as the drug treatment group. 1 μL of DMSO was added to the blank control, while 1 μL of a 3-fold serially diluted positive control and test compound were added to the positive control and drug treatment groups, respectively, resulting in a final concentration of 0–1000 nM. After 24 h of culture, cell lysis samples were collected into 1.5 mL EP tubes, centrifuged at 12,000 rpm for 15 min at 4°C, and then quantified and prepared using the BCA method. The cells were then heat-denatured in a metal bath at 95°C for 5 min. Protein samples were electrophoresed on a 12% precast gel. After the protein bands separated, they were transferred to a 0.45 μm PVDF membrane using a transfer apparatus. The membrane was blocked with 5% skim milk powder for 1 h, and then primary antibodies (anti-IKZF2 1:1000 (CST cat#:89270S) and anti-ACTIN 1:1000 (CST cat#:4970s, Beyotime cat#:AF5003) were added. The membrane was incubated overnight at 4°C. The next day, the membrane was washed three times with TBST, and then the secondary fluorescent antibody (Goat anti-Rabbit 1:30000 (Thermo cat#:A32735)) was added. The membrane was incubated at room temperature for 1 h, and then washed three more times with TBST. Finally, the membrane was exposed using a gel imaging system (LI-COR, Odyssey CLx System). The bands were analyzed using ImageStudio, and the data were processed using GraphPad Prism 8.0.

[0621] JurKat cells were cultured in RPMI 1640 (ATCC, 30-2001) complete medium containing 10% FBS (Hyclone, SH30406.05). Cells were seeded at a density of 500,000 cells per well in 6-well plates (2 mL). A 0.5‰ DMSO solution served as the blank control, DKY709 as the positive control, and the test compound as the treatment group. 1 μL of DMSO was added to the blank control, while 1 μL of 0–2 mM serially diluted positive control and test compound (3-fold dilution) were added to the positive control and treatment groups, respectively, resulting in a final concentration of 0–1000 nM. After 24 h of culture, cells were collected by centrifugation at 1000 rpm. The supernatant was discarded, and 40 μL of cell lysis buffer was added to each tube. Cells were lysed on ice for 15–20 min, centrifuged at 12000 rpm for 15 min at 4 °C, and then quantified and prepared using the BCA method. The cells were then heat-denatured in a metal bath at 95 °C for 5 min. Protein samples were subjected to electrophoresis on a 12% precast gel. After the protein bands separated, the proteins were transferred to a 0.45 μm PVDF membrane using a transfer apparatus. The membrane was blocked with 5% skim milk powder for 1 h, and then primary antibodies (anti-IKZF2 1:1000 (CST cat#:89270S) and anti-ACTIN 1:1000 (CST cat#:4970s, Beyotime cat#:AF5003) were added. The membrane was incubated overnight at 4°C. The next day, the membrane was washed three times with TBST, and then the secondary fluorescent antibody (Goat anti-Rabbit 1:30000 (Thermo cat#:A32735)) was added. The membrane was incubated at room temperature for 1 h, and then washed three more times with TBST. Finally, the membrane was exposed using a gel imaging system (LI-COR, Odyssey CLx System). The bands were analyzed using ImageStudio, and the data were processed using GraphPadPrism 8.0.

[0622] Human Treg cells (Ausun Biotech, FPB009-4F-C) were purchased, revived, and stimulated with CD3 / CD28 magnetic beads for 3 days at a cell-to-bead ratio of 1:4. Cell status was observed daily, and cells were expanded and passaged. Cells were then seeded at 500,000 cells per well in 24-well plates. The drug was diluted 3-fold with 1 μM and treated for 24 hours. Cells were then collected for Western blotting.

[0623] Table 8 Degradation activity against IKZF2 protein Note: DC 50 (nM) represents the concentration of the compound that degrades 50% of the ERα protein; D max (%) represents the maximum degradation rate achievable by the compound within the tested concentration range; AUC degr Area under the blood drug concentration-time curve; D @1000nM(%) represents the degradation rate (%) when the compound concentration is 1000 nM.

[0624] The exemplary compounds of this invention have strong degradation activity against IKZF2 protein.

[0625] Experimental Example 8: Jurkat Cell IL-2 Secretion Assay

[0626] JurKat cells were cultured in RPMI 1640 (ATCC, 30-2001) complete medium containing 10% FBS (Hyclone, SH30406.05). Cells were seeded at a density of 50,000 cells per well in 96-well plates. Different concentrations of the compound and the positive control sample NVP-DKY709 (purchased from Bio-Tech) were prepared and co-treated with 2 μg / mL phytohemagglutinin-L (PHA-L) (Thermo, 00-4977-93). Cells were incubated at 37°C in a 5% CO2 cell culture incubator for 24 h. After 24 h, the cell supernatant was collected by centrifugation at 2000g for 10 min, and the IL-2 secretion level in JurKat cells was measured using a human IL-2 ELISA kit (R&D system, D2050).

[0627] Table 9 Results of IL-2 secretion level test in Jurkat cells

[0628] The results show that the exemplary compounds of the present invention can promote the secretion of IL-2 by Jurkat cells.

[0629] Test Example 9: Repression Test of Downstream Gene Transcription

[0630] MCF-7 or T-47D cells were trypsinized and seeded in 6-well plates using phenol red-free DMEM or RPMI 1640 medium with 10% activated charcoal-adsorbed serum. After 48 hours of hormone-free treatment, the medium was replaced with a final concentration of 1 nM estrogen, and the cells were treated with different concentrations of the compound for 24 or 48 hours. RNA was extracted from the cells using an automated nucleic acid extraction and purification system (TIANGEN, TGuide S16) and a TGuide S32 magnetic bead total RNA extraction kit (TIANGEN, DP661). RNA was then reverse transcribed into cDNA using a reverse transcription system (BIO-RAD, C1000) and a FastKing cDNA first-strand synthesis kit (TIANGEN, KR116-02). Real-time quantitative PCR was performed using a qPCR system (BIO-RAD, CFX96) and FastReal rapid real-time PCR premixed reagent (TIANGEN, FP217-02). The data detected by the instrument is calculated using the following methods: ΔCT = CT (target gene) - CT (reference gene), ΔΔCT = ΔCT (target sample) - ΔCT (reference sample), and the ratio of the drug-treated group to the control group is: ratio = 2. -ΔΔCT The ratio represents the remaining gene expression level in cells after drug treatment, so the inhibition rate is 1 minus this ratio. The data was then plotted using GraphPadPrism 8.0.1. The experimental results are shown in Tables 10 and 11. The tested ER target genes GREB1 and PGR demonstrate ER signal transduction.

[0631] Table 10 Note: ND indicates not detected.

[0632] Table 11

[0633] The results showed that the exemplary compound of the present invention significantly improved the degradation rate of ERα in different cell lines compared with the control compound.

[0634] Experiment 10: Repression of Downstream Gene Transcription

[0635] Resuspend cells in a complete culture medium containing phenol red-free medium and 10% activated charcoal to adsorb serum; follow the regimen of 2 × 10⁻⁶ cells / day. 5 Each well is seeded with one sample of the same sample and treated in a 6-well plate under hormone-free conditions for 48 hours. Then, the old medium is discarded, and 2 ml of phenol red-free medium + 10% activated charcoal-adsorbed serum complete medium is added to each well.

[0636] Wild-type cells were divided into an estrogen group and an estrogen plus compound group, and continued to be treated for 24 h (MCF-7 cells and ZR-75-1 cells, estrogen 1 nM) or 48 h (T-47D cells, estrogen 10 nM).

[0637] MCF-7 Y537S Cells, MCF-7 D538G Cells and T-47D D538G Cells were divided into a DMSO group and a drug-treated group (mutant cells with activated ER did not require separate estrogen stimulation of downstream gene expression) and treated for 24 h (MCF-7 mutant cells) or 48 h (T-47D mutant cells). Cellular RNA was extracted using an automated nucleic acid extraction and purification system (TIANGEN, TGuide S16) and a TGuide S32 magnetic bead total RNA extraction kit (TIANGEN, DP661). RNA was reverse transcribed into cDNA using a reverse transcription system (BIO-RAD, C1000) and a FastKing cDNA first-strand synthesis kit (TIANGEN, KR116-02). Real-time quantitative PCR was performed using a qPCR system (BIO-RAD, CFX96) or a qPCR system (Thermo, ABI7500) and FastReal rapid real-time PCR premixed reagent (TIANGEN, FP217-02). Data analysis was performed using GraphPadPrism 8.0.1.

[0638] Table 12. Repression of transcription of downstream genes of ER (%)

[0639] The results show that the exemplary compounds of the present invention have a good inhibitory effect on the transcription of downstream genes of ER.

[0640] Experiment 11: Affinity test of target protein and E3 ubiquitin ligase

[0641] Use Biacore TMThe affinity of compounds for proteins was tested using the 8K SPR system (Cytiva). ERα protein (Thermofisher, cat#A15674) was immobilized on a CM5 (Cytiva, cat#BR100050) chip using an amino-coupling kit (Cytiva, cat#BR100050) in (10 mM PBS, pH 7.4, 137 mM NaCl, 2.7 mM KCl, 1 mM TCEP, 0.005% TWEEN-20). Then, serially diluted compounds were sequentially flowed through the chip in a running buffer (10 mM HEPES, pH 7.0, 150 mM NaCl, 1 mM TCEP, 0.005% TWEEN-20, 3% DMSO) in a multi-cycle mode at a flow rate of 30 μL / min, with binding for 100 s and dissociation for 150 s. The binding rate constant K was calculated using the instrument's built-in analysis software. on dissociation rate constant K off and dissociation constants KD, K D =K off / K on steady-state correlation K D The model calculation is obtained by directly fitting the curve calculated by the software, and the cooperation α = [K D (Compound, 1:1 binding kinetics) +K D (Compound, steady-state correlation)] / [K D (Compound + CRBN, 1:1 binding kinetics) + K D [(Compound + CRBN, steady-state correlation)]; Cooperativity α is the ratio of the affinity KD of the compound to ERα to the affinity KD of the compound + CRBN to ERα. Cooperativity α > 1 indicates a greater likelihood of forming a ternary complex of compound + CRBN + ERα, while Cooperativity α < 1 indicates a greater likelihood of forming a binary complex of compound + ERα. A larger Cooperativity α indicates a stronger ability to form ternary complexes. The formula for calculating Cooperativity α is:

[0642] Table 13 Affinity to target protein ERα

[0643] The compounds of this invention have comparable or better affinity for the target protein ERα compared to the positive control compounds.

[0644] 2. Experimental methods and principles for the affinity of IKZF2:

[0645] Use BiacoreTM The affinity of compounds for proteins was tested using an 8K SPR system (Cytiva). CRBN protein (custom expression by GenScript) was immobilized on a CM5 (Cytiva, cat#BR100050) chip in buffer (10 mM PBS, pH 7.4, 137 mM NaCl, 2.7 mM KCl, 1 mM TCEP, 0.005% TWEEN-20) using an amino-co-conjugation kit (Cytiva, cat#BR100530). Then, serially diluted compounds were co-incubated with 0 nM or 10 nM IKZF2 (abcam, ab204211) in a running buffer of 20 mM Bicine, 100 mM KCl, and 5 mM MgCl2. 2， The solution was sequentially flowed through the chip in a multi-cycle mode in 0.1 mM TCEP, 0.05% TWEEN-20, and 4% DMSO at a flow rate of 50 μL / min, with binding for 100 s and dissociation for 300 s. K was calculated using the instrument's built-in analysis software. on K off K D NVP-DKY709 (purchased from Bid Pharmaceuticals).

[0646] Table 14 Affinity to target protein IKZF2

[0647] The compound of this application has a significantly better affinity for the target protein IKZF2 compared to the positive control compound.

[0648] 3. Experimental methods and principles for the binding affinity of E3 ubiquitin ligase CRBN:

[0649] The binding affinity of the compound to CRBN protein was detected using the CRBN HTRF kit (Revvity, 64BDCRBNPEG). 5X diluent was diluted with deionized water to 1X diluent; GST Eu Cryptate Antibody and Thalidomide-Red reagent were diluted separately to 1X working solutions using PROTAC binding buffer; Human Cereblon WT GST-tagged was diluted with 1X diluent to prepare a 1X CRBN protein solution; 10 mM of the test compound (DMSO solution) was serially diluted 5-fold with 1X diluent buffer to create 8 concentration gradients (the final concentration in the reaction system should not exceed 200 μM), meaning the highest concentration should be an 800 μM compound solution. Add 5 μL of 4X compound working solution, 5 μL of CereblonWT Protein, 5 μL of LST Eu Cryptate Antibody, and 5 μL of Thalidomide-Red reagent to each well sequentially. For the control group, add 10 μL of donor + receptor + 5 μL of protein + 5 μL of diluent. For the negative control group, add 10 μL of donor + receptor + 5 μL of 1X binding buffer + 5 μL of diluent. For the background control, add 15 μL of 1X binding buffer + 5 μL of diluent. Incubate on a shaker at room temperature for 3 hours, then read the plate. Measure the fluorescence values ​​of the donor and receptor in each well. After subtracting the fluorescence values ​​of the background wells, calculate the receptor-to-donor ratio based on the fluorescence values ​​of the sample groups: Ratio = Signal(665nm) / Signal(620nm) × 10000. Perform curve fitting using GraphPad Prism 8.0 and calculate the IC50. 50 value.

[0650] Table 15

[0651] The exemplary compounds of this invention exhibit significantly better CRBN binding affinity compared to the positive control compounds.

[0652] Experiment 12: Co-culture of MCF-7 or MDA-MB-231 with PBMC

[0653] MCF-7-luc (CBP30105L) or MDA-MB-231 (ATCC, HTB-26) cells were seeded at a density of 20,000 cells per well in 96-well plates using DMEM (Gibco, 11995-065) complete medium containing 10% fetal bovine serum (Hyclone, SH30406.05). Cells were incubated overnight at 37°C in a 5% CO2 incubator. The next day, the medium was aspirated, and cells were added using CTS. TM OpTmizer TM T cell expansion: Human and human peripheral blood mononuclear cells (PBMCs) (Ausnutria Biotechnology, FPB003F-C) were resuspended in SFM medium at 40,000 cells / well. Different concentrations of compounds and a positive control sample, NVP-DKY709, were prepared to treat the cells. On the third day, Anti-CD3 30 ng / mL was added, and the cells were incubated at 37°C in a 5% CO2 incubator for another 5 days. Afterwards, Bright-Lite was used... TM MCF-7-luc cell viability was detected using the Luciferase Assay System kit (Vazyme, DD1204-01), and MDA-MB-231 cell viability was detected using the CellTiter-Glo kit (Promega, G9242).

[0654] Table 16

[0655] Table 17

[0656] The results showed that in the co-culture system with PBMCs, after adding Anti-CD3 to activate T cells, but without the compound (0 nM group), the activated PBMCs inhibited MCF-7 or MDA-MB-231 cells by 27%-33%. However, as the concentration of the compound applied in this application increased, the killing effect of immune cells on tumor cells became stronger, indicating that the compound applied in this application inhibits the immunosuppressive effect of Tregs by degrading IKZF2, thereby increasing the killing effect of effector T cells on tumor cells.

[0657] Experimental Example 13: In vivo efficacy test

[0658] 1. MCF-7 WT xenotransplantation model

[0659] Seven-week-old NOD SCID female mice (Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.) had 1.7 mg of 90-day sustained-release 17β-estradiol tablets (Innovative Research of America) subcutaneously embedded in the right side of their necks. Three days later, each mouse was subcutaneously injected with 100 μL of MCF-7 cells (containing 50% Corning standard matrix gel, cat#:354234) on the right side of its back, with a cell count of 1×10⁻⁶ cells. 7 1 cell / tumor. Tumor growth is monitored regularly until the average tumor volume reaches 200 mm². 3 Dosing began around 2:00 AM. Administered once daily for 21 consecutive days (qd×21), with an oral gavage volume of 10 mL / kg per animal. The solvent was DMSO:PEG200:30% SEB-β-CD = 5:20:75. In the efficacy study, tumor volume and body weight were measured three times weekly to calculate tumor growth inhibition (TGI). Whole blood samples were collected from the orbital sinus at 1, 2, 4, 6, 8, and 24 hours after day 21 of administration to test the pharmacokinetic endpoint (PK). Tumor samples were also collected to test drug concentration within the tumor. Tissue distribution experiments were performed using the same blood sampling method.

[0660] 2. T-47D WT xenotransplantation model

[0661] Six-week-old female B-NDG mice (Biocytok Pharmaceuticals Co., Ltd.) had 1.7 mg of 90-day extended-release 17β-estradiol tablets (Innovative Research of America) subcutaneously embedded in the right side of their necks. Three days later, each mouse received a subcutaneous injection of 200 μL of T-47D cells (containing 50% ABW matrix gel, cat#:082724) in the posterior axilla, with a cell count of 1 × 10⁻⁶ cells. 7 1 cell / tumor. Tumor growth is monitored regularly until the average tumor volume reaches 200 mm². 3 Dosing began around 2:00 AM. Administered once daily for 28 consecutive days (qd×28), according to the dosage listed in Table 19. Abemaciclib (a marketed drug) was purchased through regular channels. Each animal was administered the drug orally via gavage, using a solvent of DMSO:PEG200:30% SEB-β-CD = 5:20:75. In the efficacy study, tumor volume and body weight were measured three times weekly to calculate the total glycation index (TGI). Whole blood samples were collected from the orbital cavity at 1, 2, 4, 6, 8, and 24 hours after day 28 of administration to test the pharmacokinetic endpoint (PK), and tumor samples were taken to test the drug concentration in the tumor.

[0662] 3. T-47D D538G xenotransplantation model

[0663] Six-week-old female B-NDG mice (Biocytok Pharmaceuticals, Inc.) had 1.7 mg of 90-day extended-release 17β-estradiol tablets (Innovative Research of America) subcutaneously implanted in the right side of their necks. Three days later, each mouse was subcutaneously injected with T-47D in the posterior axillary region. D538G 200 μL of cells (containing 50% ABW matrix gel, cat#: 082724) were injected, with a cell count of 1 × 10⁻⁶ cells. 7 1 cell / tumor. Tumor growth is monitored regularly until the average tumor volume reaches 200 mm². 3 Dosing began around 24 hours prior to administration. Administered once daily for 28 consecutive days (qd×28), the oral gavage volume per animal was 10 mL / kg, and the solvent was DMSO:PEG200:30% SEB-β-CD = 5:20:75. In the efficacy study, tumor volume and body weight were measured three times weekly to calculate the total glycemic index (TGI). Whole blood samples were collected from the orbital sinus at 1, 2, 4, 6, 8, and 24 hours after day 28 of administration to test the pharmacokinetic endpoint (PK), and tumor samples were taken to determine the drug concentration within the tumor.

[0664] Tumor growth inhibition (TGI) calculations for each group are as follows:

[0665] TGI% = [1-(T i -T0) / (C i -C0)]×100, where, T i Let T0 be the average tumor volume of the treatment group on day i, and C be the average tumor volume of the treatment group at the time of grouping. i Ci represents the average tumor volume of the Vehicle group on day i, and C0 represents the average tumor volume of the Vehicle group at the time of grouping. The unit of tumor volume is mm. 3 .

[0666] Tumor volume T = (long axis × short axis) 2 ) / 2, all measurements are in millimeters.

[0667] Table 18 Results of tumor growth inhibition and target protein degradation in MCF-7 model mice

[0668] Table 19 Results of tumor growth inhibition and target protein degradation in T47D model mice

[0669] Table 20 T47D- D538G Tumor growth inhibition and target protein degradation results in model mice

[0670] The results show that the exemplary compounds of this application significantly inhibit the weight growth of tumor-bearing mice and significantly improve the ER degradation rate.

[0671] Pharmacokinetic (PK) Properties of Experimental Example 14

[0672] Mice comprehensive PK test

[0673] Reagents: Acetonitrile (Fisher A998-4). Instruments: Shimadzu LC40 HPLC System for liquid chromatography, AB SCIEX X500B QTOF Platform for mass spectrometry. ICR: Female mice, 20–24 g, purchased from Vital Rivers.

[0674] The dosing regimen is shown in Table 21 below.

[0675] The experimental steps are as follows:

[0676] 1. Mice were administered the drug via gavage without fasting. Blood samples were collected from the retro-orbital venous plexus at 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, and 24 h (ER-P-1 to ER-P-3 up to 48 h) after gavage and intravenous administration, respectively. Whole blood was collected into anticoagulant tubes containing EDTA. The control compounds 1 and 2 were administered via gavage and intravenous administration using DMSO:PEG200:physiological saline at a ratio of 1:7:2. Compounds ER-P-1 and ER-P-3 were administered via gavage and intravenous administration using DMSO:solutol:H2O at a ratio of 1:1:8.

[0677] 2. Centrifuge the supernatant within 1 hour after whole blood collection at 4℃, 4000 rpm for 10 min. Store the plasma sample in a freezer at -80℃ for later use.

[0678] 3. Before analysis, remove the sample plasma and blank plasma and thaw them on ice or in a 4°C freezer.

[0679] 4. Preparation of standard curve samples: The test compounds were diluted with DMSO to the required concentration. 5 μL of the compound solution was added to 45 μL of mouse blank plasma, and 200 μL of internal standard acetonitrile (1500, 50 nM labetalol and 500 nM terfenadine) was added to precipitate the protein. The mixture was centrifuged at 3200 rpm for 40 min. The standard curve was set with 8-10 concentration gradients.

[0680] 5. Prepare quality control samples according to the standard curve preparation method, and set four quality control samples with lower limit of quantitation and high, medium and low concentrations. Each quality control sample should be replicated in triplicate.

[0681] 6. Take 50 μL of plasma samples from different time points and add 200 μL of internal standard acetonitrile to precipitate proteins.

[0682] 7. After centrifugation of the standard curve samples, quality control samples, and plasma samples at different time points, 100 L of the supernatant was diluted 1:1 with water and analyzed by LC-MS / MS. The plasma concentrations of the compound at different time points were calculated using Excel. The pharmacokinetic parameters in the table below were calculated using Phoenix WinNonlin. The specific experimental results are shown in Table 21.

[0683] Table 21. Pharmacokinetic parameters of the exemplary compounds disclosed herein in mice. Note: "-" indicates not applicable; iv is for intravenous administration; po is for oral administration; Cl obs V represents the system clearance rate. ss_obs Let C0 be the steady-state distribution volume, and T be the extrapolated zero-time blood drug concentration. max To reach peak time, C max To reach peak concentration, AUC last The area under the drug-time curve (AUC) is the time from zero to the final quantifiable concentration. INF _ obs Let F( be the area under the curve from time 0 to infinity) 0-last () represents bioavailability.

[0684] A comprehensive comparison test of compound ER-P-1 with beagles

[0685] Reagent: Acetonitrile (Fisher A998-4). Instruments: Shimadzu LC40 HPLC System for liquid chromatography; AB SCIEX X500B QTOF Platform for mass spectrometry. Beagle: 7–8 kg, 7–8 months old, female, purchased from Changyang Xishan Breeding Farm.

[0686] The experimental steps are as follows:

[0687] 1. After oral administration to beagles on an empty stomach, whole blood samples were collected from the cephalic vein of the forelimb or the saphenous vein of the hindlimb at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h, and 96 h after administration; after intravenous administration, whole blood samples were collected from the cephalic vein of the forelimb or the saphenous vein of the hindlimb at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h, and 96 h (or 120 h) after administration. The whole blood was collected in anticoagulant tubes containing EDTA. Beagles were administered 5 or 10 mg / kg orally, or 1 mg / kg intravenously. The solvent for both oral and intravenous administration was DMSO:PEG200:physiological saline = 1:7:2 (for ER-P-1, the solvent for oral administration was propylene glycol:(0.5% CMC-Na containing 0.2% SDS) = 2:8).

[0688] 2. Blood Sample Processing and Testing: After whole blood collection, the sample was thoroughly mixed by inverting the container multiple times. The supernatant was collected by centrifugation within 1 hour at 4000 rpm for 10 minutes. The obtained plasma sample was stored at -80℃ and tested according to the steps outlined in the mouse comprehensive PK test section. The PK parameters in the table below were calculated. The experimental results are shown in Table 22.

[0689] Table 22 Beagle Pharmacokinetic Parameters of Exemplary Compounds of this Disclosure Note: "-" indicates no test results.

[0690] The results showed that the compound of the present invention significantly improved the PK properties in animals compared with the control compound.

[0691] A comprehensive comparison test of compounds ER-P-3 and ER-P-19 with beagles

[0692] The experimental procedure was as follows: After beagle dogs were administered the drug via gavage on an empty stomach, whole blood was collected from the cephalic vein of the forelimb or the saphenous vein of the hindlimb at 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, 12 h, 24 h, 48 h, 72 h, and 96 h after administration; after intravenous administration, whole blood was collected from the cephalic vein of the forelimb or the saphenous vein of the hindlimb at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h, 24 h, 48 h, 72 h, and 96 h after administration. Whole blood was collected in anticoagulant tubes containing EDTA. Beagles were administered 5 mg / kg orally (po) and 1 mg / kg intravenously (iv). The solvent for gavage and intravenous administration was DMSO:PEG200:physiological saline = 1:7:2; the solvent for ER-P-3 and ER-P-19 gavage was propylene glycol:(0.5% CMC-Na containing 0.2% SDS) = 2:8. Blood sample processing and testing: After whole blood collection, the sample was thoroughly mixed by inverting the container multiple times. The supernatant was collected by centrifugation within 1 hour at a speed of 4000 rpm for 10 minutes. The obtained plasma sample was stored at -80°C and tested according to the steps in the mouse comprehensive PK test section above. The PK parameters in the table below were calculated.

[0693] Table 23 PK Parameters in Beagles Note: "-" indicates no test results.

[0694] The results showed that the compound of the present invention significantly improved the PK properties in animals compared with the control compound.

[0695] Experiment 15: Cytochrome P450 isoenzyme (CYP) inhibition experiment

[0696] Reagents: Pooled human liver microsomes (Cat#452117) were purchased from Corning, and NADPH (Cat#N8100) was purchased from Solarbio Science & Technology Co., Ltd. Instrument: AB SCIEX LC-MS instrument (5049811).

[0697] The experimental steps are as follows:

[0698] 1. Incubation system

[0699] Table 24

[0700] 2. Mix the above incubation system with 0.5 μL of each subenzyme-specific substrate separately, and pre-incubate at 37°C for 5 min. The substrate concentrations are as follows: phenacetin (CYP1A2) 75 μM, diclofenac (CYP2C9) 10 μM, S-metphenytoin (CYP2C19) 20 μM, dextromethorphan (CYP2D6) 10 μM, testosterone (CYP3A4) 40 μM, bupropion (CYP2B6) 80 μM, and amodiaquine (CYP2C8) 2 μM. Add 1 μL of inhibitor / analyte compound to the pre-incubation system. The inhibitors corresponding to each subenzyme are diluted with DMSO to prepare a series of concentration gradients. The inhibitor concentrations are as follows: α-naphthylflavonoid (CYP1A2) 0-1 μM, sulfadiazine (CYP2C9) 0-10 μM, and (S)-(+)-N-benzylphenanol (CYP2C19).

[0701] Quinidine (CYP2D6) 0-10 μM, ketoconazole (CYP3A4) 0-1 μM, ticlopidine (CYP2B6) 0-10 μM, montelukast (CYP2C8) 0-10 μM, and the analyte concentrations were 0-30 μM. The compounds were three-fold diluted, resulting in seven concentrations. The reaction was initiated by adding 20 μL of 10 mM NADPH to the pre-incubated system. The mixture was incubated at 37°C for 10 min for CYP1A2, CYP2C9, CYP3A4, CYP2B6, and CYP2C8, and for 20 min for CYP2C19 and CYP2D6. The reaction was terminated by adding 80 μL of acetonitrile (3 times its volume) as the internal standard. The mixture was vortexed and centrifuged at 4°C for 30 min. The supernatant was then analyzed by LC-MS to determine the amount of metabolites generated. The experimental results are shown in Table 25.

[0702] Table 25 Results of Cytochrome P450 Isoenzyme Inhibition Experiment

[0703] The results show that the exemplary compounds of this application do not inhibit a variety of substrates, and the inhibition of CYP2B6 disappears compared to the control compounds.

[0704] Experimental Example 16: Metabolic Stability Test of Liver Microsomes

[0705] Experimental methods and principles for the identification of liver microsomal metabolites:

[0706] Microsomes: Pooled human liver microsomes (Corning Cat#X008070), Pooled CD-1 male mouse liver microsomes (Corning Cat#452701), Pooled male SD rat liver microsomes (Corning Cat#452501), Pooled male Cynomolgus monkey liver microsomes (Corning Cat#452413), Pooled male Beagledog liver microsomes (Corning Cat#452601), NADPH (Solarbio Cat#N8100), 96-well plates (Thermo Cat#260251), Instrument: Mass spectrometry (AB SCIEX X500B QTOF Platform). Data analysis was performed using MetabolitePilot 2.0 License software for metabolite identification.

[0707] The experimental steps are as follows:

[0708] 1. Prepare solutions fresh each time. Prepare 10 mM NADPH solution, 200 mM PBS solution (pH 7.4), 50 mM MgCl2 solution and 1 mM stock solution of the test compound. Prepare a 10 μM standard of the compound using 50% ACN.

[0709] 2. Add 500 μL of PBS solution, 100 μL of MgCl2 solution, and 240 μL of water to each well of a 96-well plate. Remove human, rat, mouse, beagle dog, and cynomolgus monkey liver microsomes from -80°C, thaw them on ice, and add 50 μL of 20 mg / kg liver microsomes to each system. Pre-incubate in a 37°C water bath for 2 min, then remove and add 100 μL of NADPH and 10 μL of the compound (final concentration 10 μM) to start the reaction. Mix manually. Perform duplicates for each sample and incubate in a 37°C water bath.

[0710] 3. Take 400 μL of the incubated reaction system at 0 and 60 min respectively, and mix the two parallel samples into 4 times the volume of ACN. Shake for 2 min to precipitate the protein. Centrifuge the sample at 3500 rpm for 30 min at 4 °C. Take 90% of the total volume of the supernatant, dry it with nitrogen at 37 °C, and reconstitute it with 50% acetonitrile (v / v) at 1 / 18 of the supernatant volume before analysis. The analytical samples include the system of compound incubated in human, rat, mouse, beagle dog and cynomolgus monkey liver microsomes for 0 min and 60 min respectively, as well as compound standards.

[0711] 4. The raw data were imported into MetabolitePilot 2.0 software for processing. General parameters and compound specificity parameters were set, and a data analysis batch was established. The parent drug was identified based on the retention time of the standard and the secondary chromatogram. The processed results were filtered by secondary similarity to find metabolites with primary mass spectrometry deviations within 5 ppm and secondary characteristic fragment ions and fragmentation patterns similar to the parent drug. The experimental results are shown in Table 26.

[0712] Table 26. Identification results of liver microsomal metabolites

[0713] Note: The percentage of linker deoxyalkylation metabolites refers to the ratio of the linker of a compound to the total compound after the linker breaks down due to deoxyalkylation. The lower the percentage, the higher the stability of liver microsomes. The ratio of linker breakage due to other reasons (such as oxidation or N-dealkylation) to the total compound is around 1%, and there is little difference between the control compound and the exemplary compound.

[0714] For example, the metabolite that breaks down after the deoxyalkylation reaction of control compound 1 is: The metabolites that break down after the deoxyalkylation of ER-P-1 are: The metabolites that break down after the oxidation of control compound 1 may be, for example, the following: The metabolites that break down after N-dealkylation may be, for example, […].

[0715] The results show that, compared with the control compound, the exemplary compounds ER-P-3 and ER-P-1 of the present invention significantly improved the metabolic stability of human liver microsomes by introducing F onto the benzene ring in the tricyclic fused ring structure of the left-side antagonist, and significantly reduced the content of deoxyalkylated metabolites with linker cleavage.

[0716] Experimental Example 17: Tissue Distribution in the MCF-7 Xenograft Model

[0717] Seven-week-old NOD SCID female mice (Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd.) had 1.7 mg of 90-day sustained-release 17β-estradiol tablets (Innovative Research of America) subcutaneously embedded in the right side of their necks. Three days later, each mouse was subcutaneously injected with 100 μL of MCF-7 cells (containing 50% Corning standard matrix gel, cat#:354234) on the right side of its back, with a cell count of 1×10⁻⁶ cells. 7 1 cell / animal. Tumor growth is monitored regularly, and the tumor is used when it reaches an average volume of 400 mm². 3 The drug was administered once every two hours. The solvent was DMSO:PEG200:30% SEB-β-CD = 5:20:75. Whole blood samples were collected from the orbital cavity at 6 and 24 hours after administration, and tumor samples were taken to test the drug concentration in the tumor. The experimental results are shown in Table 27.

[0718] Table 27 Concentrations of the disclosed compounds in MCF-7 xenografted NOD SCID female mice

[0719] The results showed that the compound of this application significantly increased the T / P ratio in tumor-bearing mouse tissues compared with the control compound.

[0720] The present invention has been described through the above embodiments. However, it should be understood that the above embodiments are for illustrative purposes only and are not intended to limit the invention to the scope of the described embodiments. Furthermore, those skilled in the art will understand that the present invention is not limited to the above embodiments, and many more variations and modifications can be made based on the teachings of the present invention, all of which fall within the scope of protection claimed by the present invention. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

The compound represented by formula (II): CLM―L―PTM (Ⅱ), Or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, in: CLM is the ubiquitin-binding site of the cerebellar protein E3; L is the bond that covalently connects the CLM and PTM, or -(B L ) q -; PTM is the binding site that targets the estrogen receptor protein, and it comprises the structure shown in formula (III): In the formula, R1 and R2 are each independently selected from N or CR. mm ; R3 is selected from H, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally substituted by 1, 2, 3, 4, or 5 substituents each independently selected from carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl; R4 is selected from N or CR m4 ; R5 is selected from N or CR m5 ; R6 is selected from N or CR m6 ; R7 is selected from N or CR m7 ; R mm R m8 R m9 R m10 and R m11 Each time it appears, it is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl; or R m4 and R m5 Each time it appears, it is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl; or R m4 and R m5 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloyl group, C6-C 10 The aryl group is substituted with one or more substituents of a 5-10 member heteroaryl group; or R4 is CR. m4 When R5 is N, R m4 R5 and R m4 The attached carbon atoms form 4-10 membered heterocyclic alkyl groups containing 1-3 heteroatoms, each independently selected from N, O, and S; R m6 and R m7 Each time it appears, it is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl; or R m6 and R m7 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, C6-C 10 Aryl, C5-C 10 Substituted by one or more substituents in heteroaryl and 5-10 membered heteroaryl; In the PTM, when R1 and R2 are both CH, R m9 When H is present, (a)R m4 and R m5 And the atoms they are connected to form saturated or unsaturated ring structures, or (b)R m6 and R m7 The carbon atoms to which they are attached form a saturated or unsaturated ring structure, or (c) one of R4 and R6 is selected from N; preferably at least one of R4 and R6 is selected from N; or R mm R m8 and R m9 At least one of them is not H in each occurrence; B L Each occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, SO, SO2, NR L3 SO2NR L3 SONR L3 C(O)NR L3 NR L3 C(O)NR L4 NR L3 SO2NR L4 C(O), CR L1 =CR L2 C≡C, SiR L1 R L2 P(O)R L1 P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 0-6 R groups. L1 and / or R L2 Group substitution; R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, C. 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, C(O)-C 3-8 Cycloalkyl, C(O)-C 3-11 Heterocyclic, O-aryl, O-heteroaryl, SC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, N(C) 3-8 cycloalkyl)2, N(C) 3-8 cycloalkyl)(C 1-8 Alkyl), N(C) 1-8 Alkylene)(C 3-8 cycloalkyl), NH-C 3-8 Heterocyclic groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8 Heterocyclic group)(C 1-8 Alkyl), NH-aryl, N(aryl) (C 1-8 Alkyl), NH-heteroaryl, N(heteroaryl) (C 1-8 Alkyl), OH, NH2, SH, SO2P(O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, C(O)-C 1-8 Alkyl, C(O)OC 1-8 Alkyl, C(O)2H, CN, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C) 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C) 1-8 Alkyl)2、C(O)NH-C 1-8 Alkyl, C(O)NH-C 3-8 cycloalkyl, C(O)NH-C 3-11 Heterocyclic groups, C(O)N(C) 1-8 Alkyl)2, N(C) 1-8 alkyl)C(O)NH(C 1-8 Alkyl), N(C) 1-8 alkyl)C(O)N(C 1-8 Alkyl)2、NHC(O)NH(C 1-8 Alkyl), NHC(O)N(C 1-8 Alkyl)2, NHC(O)NH2, N(C) 1-8 alkyl)SO2NH(C 1-8 Alkyl), N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 Alkyl), NH SO2N (C 1-8 Alkyl)2 and NH SO2NH2, optionally, wherein the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic group, C 6-10 The aryl and 5-10 heteroaryl groups are each independently substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxyl, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloyl, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl and haloheteroaryl; q is an integer greater than or equal to 1; Preferably, the CLM comprises a structure selected from the following: Among them, W 1 and W 2 Each independently for CR a R b C (=O), NR a Or SO2, and W 1 and W 2 At least one of them is C (=O); G and Z are each independently selected from O, S, and Se; W 5 W 6 Each occurrence is independently C(R) m 2. NR m , O or S; W 11 For CR a R b C (=O), NR a Or SO2; R8, R9, R a R m R N and R b Each time it appears, it is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl and C1-C6 alkylNHacyl; R 22 Selected from single bonds, C(O), O, S, SO2, -NR m -、-NR m Combinations of one or more of C(O)-, alkylene, alkenylene, ynylene, haloalkylene, and heteroalkylene; n is 0, 1, 2, or 3; R 32 and R 42 Together with the carbon atoms attached to it, it forms And R 52 R 62 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C2-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups; or R 42 and R 52 Together with the carbon atoms attached to it, it forms And R 32 R 62 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C2-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups; or R 52 and R 62 Together with the carbon atoms attached to it, it forms And R 32 R 42 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C2-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups; R d R e R f R g R D R E R F R G R f1 R g1 R F1 and R G1 Each occurrence is independently C(R) m 2. NR m O, C(O) or S; W 3 and W 4 Each independently for CR m Or N; R t R T R t1 R T1 Each independently for CR m Or N, R t R T R t1 R T1 Side connection Represents the connection site between CLM and L; Each occurrence of m1 and m2 is independently 0, 1, 2, 3, 4, 5 or 6, and m1 + m2 ≤ 6; m3 appears each time as 0, 1, 2, 3, 4, 5, 6 or 7, m4 appears each time as 1, 2, 3, 4, 5, 6, 7 or 8, and m3 + m4 ≤ 8; Each occurrence of m5 and m6 is independently 0, 1, 2, 3, 4, 5, 6 or 7, and m5 + m6 ≤ 7; Each occurrence of m7 and m8 is independently 0, 1, 2, 3, 4, 5, 6 or 7, and m7 + m8 ≤ 7; m31 is an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m41 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8, and m31 + m41 ≤ 8; and m51 is an integer of 0, 1, 2, 3, 4, 5, 6 or 7, m61 is an integer of 1, 2, 3, 4, 5, 6, 7 or 8, and m51 + m61 ≤ 8. The compound of claim 1, wherein, R1 is CR mm ; and / or R2 is CR mm ; and / or R3 is R m1 R m2 and R m3 Each occurrence is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylNHacyl; preferably, R m1 R m2 and R m3 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; more preferably, R m1 R m2 and R m3 Each occurrence is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups; more preferably, R m1 R m2 and R m3 Each occurrence is independently of H, C1-C3 alkyl, F, Cl, Br, or I; and / or R mm R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino, and R mm R m8 and R m9 Each occurrence must contain at least one non-H; preferably, R mm R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino, and R mm and R m9 Each occurrence must contain at least one non-H; more preferably, R mm R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, and R mm R m8 and R m9 Each occurrence must have at least one element that is not H; more preferably, R mm R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, and R mm R m8 and R m9 Each occurrence must have at least one element that is not H; preferably, R mm R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, and R1 is not CH; preferably, R mm R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently of H, C1-C3 alkyl, F, Cl, Br, and I, and R mm R m8 and R m9 Each occurrence must have at least one element that is not H; preferably, R mm R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently of H, C1-C3 alkyl, F, Cl, Br, and I, and R1 is not CH; preferably, R mm R m8 and R m9 Each occurrence is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, and at least one is not H; preferably, R mm R m8 and R m9 Each occurrence is independently of H, C1-C3 alkyl, F, Cl, Br, and I, and R mm and R m9 Each occurrence must have at least one element that is not H; preferably, R mm R m8 and R m9 Each occurrence is independently of H, C1-C3 alkyl, F, Cl, Br, and I, and R mm Each occurrence must have at least one element that is not H; preferably, R mm R m8 and R m9 Each occurrence is independently of H, C1-C3 alkyl, F, Cl, Br, and I, and R1 is not CH; or R m4 and R m5 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 5-7 membered cycloalkyl group or a 5-7 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the saturated or unsaturated 5-7 membered cycloalkyl group or the 5-7 membered heterocycloalkyl group is unsubstituted or substituted by one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, nitro, cyano, and amino; or R m6 and R m7 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 5-7 membered cycloalkyl group or a 5-7 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the saturated or unsaturated 5-7 membered cycloalkyl group or the 5-7 membered heterocycloalkyl group is unsubstituted or substituted by one or more substituents selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, hydroxy, nitro, cyano, and amino; or R4 is CR m4 When R5 is N, R m4 R5 and R m4 The attached carbon atom can form a 5-7 membered heterocyclic alkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S; and / or R mm and R m9 Each occurrence must contain at least one non-H; preferably, R mm At least one of them is not H in each occurrence; more preferably, R1 is not CH; and / or B L Each occurrence is independently selected from: CR L1 R L2 O, S, SO, SO2, NR L3 CO, C≡C, 3-16 cycloalkylene, 3-16 heterocyclic, 6-10 aryl, and 5-10 heteroaryl, wherein the 3-16 cycloalkylene, 3-16 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are optionally surrounded by 0, 1, 2, or 3 Rs. L1 and / or R L2 Group substitution; and / or R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, C. 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, C(O)-C 3-8 Cycloalkyl, C(O)-C 3-11 Heterocyclic, O-aryl, O-heteroaryl, SC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, N(C) 3-8 cycloalkyl)2, N(C) 3-8 cycloalkyl)(C 1-8 Alkyl), N(C) 1-8 Alkylene)(C 3-8 cycloalkyl), NH-C 3-8 Heterocyclic groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8 Heterocyclic group)(C 1-8 Alkyl), NH-aryl, N(aryl) (C 1-8 Alkyl), NH-heteroaryl, N(heteroaryl) (C 1-8 Alkyl), OH, NH2, SH, SO2P(O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, C(O)-C 1-8 Alkyl, C(O)OC 1-8 Alkyl, C(O)2H, CN, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C) 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C) 1-8 Alkyl)2、C(O)NH-C 1-8 Alkyl, C(O)NH-C 3-8 cycloalkyl, C(O)NH-C 3-11 Heterocyclic groups, C(O)N(C) 1-8 Alkyl)2, N(C) 1-8 alkyl)C(O)NH(C 1-8 Alkyl), N(C) 1-8 alkyl)C(O)N(C 1-8 Alkyl)2、NHC(O)NH(C 1-8 Alkyl), NHC(O)N(C 1-8 Alkyl)2, NHC(O)NH2, N(C) 1-8 alkyl)SO2NH(C 1-8 Alkyl), N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 Alkyl), NH SO2N (C 1-8 Alkyl)2 and NH SO2NH2, wherein the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic group, C 6-10 The aryl group and the 5-10 heteroaryl group are each independently and selectively chosen from F, Cl, Br, I, C. 1-6 Substituted by one or more substituents selected from alkyl, methoxy, and ethoxy groups; and / or q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and / or W 1 W 2 Each occurrence is independently designated as CR. a R b Or C (=O); preferably, W 1 For C (=O), W 2 For CH or W 1 For CH, W 2 For C (=O); and / or G is O; Z is O; and / or W 5 W 6 Each occurrence is independently C(R) m )2; Preferably, W 5 CH2, W 6 CH2; and / or W 11 For C (=O); and / or R8, R9, R a R m R N and R b Each of the following is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R8 and R9 are each independently H or C1-C3 alkyl, more preferably H or methyl, and more preferably H; preferably, R N It is H or C1-C3 alkyl, preferably H or methyl, more preferably methyl; and / or R 22 Selected from single bonds, C(O), NH, O, C(O)NH, NHC(O), N(C1-C3 alkyl), N(C1-C3 alkyl)C(O), C(O)N(C1-C3 alkyl) and C1-C3 alkylene; preferably, R 22 Selected from single bonds, C(O), NH, C(O)NH, NHC(O), N(CH3), N(CH3)C(O) and C(O)N(CH3); and / or n is 1; and / or R 32 and R 42 Together with the carbon atoms attached to it, it forms And R 52 R 62 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Each heteroaryl group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; preferably, R 52 R 62 and R 72 Each is independently selected from H, deuterium, halogen, C1-C3 alkyl, and C1-C3 alkoxy; or R 42 and R 52 Together with the carbon atoms attached to it, it forms And R 32 R 62 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Each heteroaryl group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted, preferably R 32 R 62 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; or R 52 and R 62 Together with the carbon atoms attached to it, it forms And R 32 R 42 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Each heteroaryl group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted; preferably, R 32 R 42 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; and / or W 3 For N, W 4 For CH or W 3 For CH, W 4 Let N be the number of elements in the array. The compound as claimed in claim 1 or 2, wherein, R1 is selected from N, CH, CF, C-Cl, C-Br and C (C1-C6 alkyl), preferably N, CH, CF or C-CH3, more preferably R1 is selected from N, CF, C-Cl, C-Br and C (C1-C6 alkyl); more preferably R1 is selected from CF, C-Cl, C-Br and C (C1-C3 alkyl); more preferably CF; and / or R2 is selected from N, CH, CF, C-Cl, C-Br and C (C1-C6 alkyl), preferably N, CH, CF or C-CH3, more preferably CH; and / or R3 is selected from C1-C3 alkyl, C1-C3 alkoxy, and halogen-substituted C1-C3 alkyl groups; preferably, R3 is selected from methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, or trifluoroethyl; preferably, R3 is difluoroethyl; preferably, R3 is CH2CHF2; and / or R4 is selected from N, CH, CF, C-Cl, C-Br, C (C1-C6 alkyl), and C (C1-C6 alkoxy), preferably N, CH, CF, C-Cl, C-Br, or C-OCH3, more preferably CF; and / or R5 is selected from N and CH, preferably CH; and / or R6 is selected from N, CH, CF, C-Cl, C-Br, C (C1-C6 alkyl), and C (C1-C6 alkoxy), preferably N, CH, CF, C-Cl, C-Br, or C-OCH3, more preferably CF; and / or R7 is selected from N and CH, preferably CH; and / or R m8 Selected from hydrogen, halogens and C1-C6 alkyl groups, preferably hydrogen, fluorine or methyl, more preferably hydrogen; R m9 Selected from hydrogen, halogens, and C1-C6 alkyl groups, preferably hydrogen, fluorine, or methyl, more preferably hydrogen; and / or R m10 Selected from hydrogen and C1-C6 alkyl groups, preferably hydrogen; and / or R m11 It is selected from hydrogen and C1-C6 alkyl groups, preferably hydrogen or methyl, more preferably methyl. The compound according to any one of claims 1-3, wherein, Selected from More preferably and / or Selected from The compound according to any one of claims 1-4, wherein, When R1, R2 and R in equation III m9 When they are not simultaneously CH, CH, and H, the values ​​in Equation III are... Selected from unsubstituted or substituted by one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino. When R1 and R2 in equation III are both CH, and R m9 When H is used, in equation III Selected from unsubstituted or substituted by one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino. Preferably, when Selected from hour, Selected from when for hour, Selected from The compound as claimed in claim 1 or 2, wherein, The PTM is selected from: The compound according to any one of claims 1-6, wherein, The CLM includes a structure selected from the following: Preferably, the CLM is selected from: Among them, W 1 W 2 W 3 W 4 W 5 W 6 W 11 R8, R9, R N R m R F R G R T R f R g R t R T1 R F1 R G1 R 32 R 42 R 52 R 62 R 72 Each of m3, m4, m31, m41, m5 and m6 is defined as described in claim 1 or 2; R 1D R 1E R 1d R 1e Each occurrence is independently selected from C(R) m 2. NR m O and C(O); R m The definition is the same as that in claim 1 or 2; Each time m1, m9 and m10 appear, they are each an independent integer of 0, 1, 2, 3, 4 or 5, and m1 + m9 + m10 ≤ 5; Each time m7, m11, and m12 appear, they are each an independent integer of 0, 1, 2, 3, 4, 5, or 6, and m7 + m11 + m12 ≤ 6; Preferably, W 1 and W 2 Each independently for CR a R b And W 1 and W 2 At least one of them is C (=O); W 3 and W 4 Each independently for CR m Or N, and W 3 and W 4 One of them is N; W 5 W 6 Each occurrence is independently C(R) m )2; R 1D R 1E R 1d R 1e Each occurrence is independently selected from C(R) m 2. NR m O and C(O); R F R G R f R g R F1 R G1 Each occurrence is independently selected from C(R) m )2; R T R t R T1 Each occurrence is independently represented by N; R8, R9, R 32 R 42 R 52 R 62 R 72 R a R b R N R m Each time it appears, it is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl and cyano groups; Each time m1, m9, and m10 appear, they are each an independent integer of 0, 1, 2, 3, 4, or 5, and m1 + m9 + m10 ≤ 5; preferably, each time m1, m9, and m10 appear, they are each an independent integer of 0, 1, or 2, and m1 + m9 + m10 ≤ 2, preferably m1 + m9 + m10 = 1, m1 + m9 + m10 = 2, or m1 + m9 + m10 = 0; Each occurrence of m7, m11, and m12 is an independent integer of 0, 1, 2, 3, 4, 5, or 6, and m7 + m11 + m12 ≤ 6; preferably, each occurrence of m7, m11, and m12 is an independent integer of 0, 1, 2, or 3, and m7 + m11 + m12 ≤ 3, preferably m7 + m11 + m12 = 2 or m7 + m11 + m12 = 1; Each occurrence of m3 and m4 is an independent integer of 0, 1, 2, 3, or 4; m3 and m4 are not both 0; m3 + m4 ≤ 5; preferably, m3 + m4 = 4, m3 + m4 = 3, or m3 + m4 = 2. Each occurrence of m5 and m6 is an independent integer of 0, 1, 2, 3, or 4; preferably, m5+m6=3, m5+m6=2, or m5+m6=1. Each occurrence of m31 and m41 is an independent integer of 0, 1, 2, 3, or 4; m31 and m41 are not both 0; m31 + m41 ≤ 5; preferably, m31 + m41 = 4, m31 + m41 = 3, or m31 + m41 = 2; and W 11 It is C (=O); Preferably, the CLM comprises a structure selected from formulas (IV-1A), (IV-1B), and (IV-1C), wherein: W 1 For C (=O), W 2 CH2 or W 1 CH2, W 2 For C (=O); preferably, W 1 For C (=O), W 2 It is CH2; W 5 W 6 Each occurrence is independently CH2, -CH(C1-C6 alkyl) and -C(C1-C6 alkyl)2; preferably, W 5 CH2, W 6 It is CH2; R8 and R9 are each independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, and hydroxyl; preferably, R8 is H and R9 is H. R 32 R 42 R 52 and R 62 Each time it appears, it is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, and cyano, more preferably H, F, Cl, Br, methyl, methoxy, or cyano; more preferably, R 32 R 42 R 52 and R 62 Each occurrence is independently represented by H; R T Let N be the number of people in the group. R F R G Each occurrence is independently selected from CH2, NH, O, and C(O); CH2 is preferred; m3 is 2; m4 is 2; R 1D R 1E Each occurrence is CH2; m7 is 0, m11 is 0, m12 is 1; or m7 is 2, m11 is 0, m12 is 0. The compound according to any one of claims 1-7, wherein, The CLM is selected from: Preferably, the CLM is selected from: The compound according to any one of claims 1-8, wherein, B L It is selected from one or more of the following structures: -O-, -S-, -SO-, -SO2-, -CH2-, -C(O)-, -NH-, -CH(CH3)-, -CH(CH2CH3)-, -C(CH3) 2 -、-N(CH3)-、-N(CH2CH3)-、 in, This is the connection site. The compound of claim 9, wherein, L is selected from the following structures: Covalent bond, -(CH2) j -、-(CH2) p -NH-(CH2) s -、-(CH2) y -NH-(CH2) j -NH-(CH2) s -、-(CH2) p -C(O)-(CH2) s -、-(CH2) p -O-(CH2) s -、-(CH2) y -C(O)-(CH2) j -C(O)-(CH2) s -、-(CH2) y -O-(CH2) j -O-(CH2) s -、-(CH2) y -O-(CH2) j -C(O)-(CH2) s -、-(CH2) p -NH-(CH2) y -O-(CH2) j -C(O)-(CH2) s -、 Each time j appears, it is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; k, s, p, and y are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; For connection sites of CLM or PTM; Preferably, L is selected from a covalent bond, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-CH2-, -NH-(CH2)2-, -NH-(CH2)3-, -NH-(CH2)4-, -NH-(CH2)5-, -NH-(CH2)6-, -NH-(CH2)7-, -NH-(CH2)8-, -C(O)-NH-CH2-, -C(O)-NH-(CH2)2-, -C(O)-NH-(CH2)3-, -C(O)-NH-(CH2)4-, -C(O)-NH-(CH2)5-, -C(O)-NH-(CH2)6-, -C(O)-NH-(CH2)7-, -C(O)-NH-(CH2)8-, -CH2-NH-, -(CH2)2-NH-, -(CH2)3-NH-, -(CH2)4-NH-, -(CH2)5-NH-, -(CH2)6-NH-, -(CH2)7-NH-, -(CH2)8-NH-, -NH-CH2-NH-, -NH-(CH2)2-NH-, -NH-(CH2)3-NH-, -NH-(CH2)4-NH-, -NH-(CH2)5-NH-, -NH-(CH2)6-NH-, -NH-(CH2)7-NH-, -NH-(CH2)8-NH-, -(CH2-CH2-O)-CH2-CH2-, -(CH2-CH2-O)2-CH2-CH2-, -(CH2-CH2-O)3-CH2-CH2-, -NH-(CH2-CH2-O)-CH2-CH2-, -NH-(CH2-CH2-O)2-CH2-CH2-, -NH-(CH2-CH2-O)3-CH2-CH2-, -C(O)-NH-(CH2-CH2-O)-CH2-CH2-, -C(O)-NH-(CH2-CH2-O)2-CH2-CH2-, -C(O)-NH-(CH2-CH2-O)3-CH2-CH2-, -(CH2-CH2-O)-CH2-CH2-NH-, -(CH2-CH2-O)2-CH2-CH2-NH-, -(CH2-CH2-O)3-CH2-CH2-NH-, -NH-(CH2-CH2-O)-CH2-CH2-NH-, -NH-(CH2-CH2-O)2-CH2-CH2-NH-, -NH-(CH2-CH2-O)3-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)-CH2-CH2-NH-, -C(O)-NH-(CH2-CH2-O)2-CH2-CH2-NH--C(O)-NH-(CH2-CH2-O)3-CH2-CH2-NH-、-CH2-CH2-(O-CH2-CH2)-、-CH2-CH2-(O-CH2-CH2)2-、-CH2-CH2-(O-CH2-CH2)3-、-NH-CH2-CH2-(O-CH2-CH2)-、-NH-CH2-CH2-(O-CH2-CH2)2-、-NH-CH2-CH2-(O-CH2-CH2)3-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)2-、-C(O)-NH- CH2-CH2-(O-CH2-CH2)3-,-CH2-CH2-(O-CH2-CH2)-NH-,-CH2-CH2-(O-CH2-CH2)2-NH-,-CH2-CH2-(O-CH2-CH2)3-NH-,-NH-CH2-CH2-(O-CH2-CH2)-NH-,-NH-CH2-CH2-(O-CH2-CH2)2-NH-,-NH-CH2-CH2-(O-CH2-CH2)3-NH-,-NH-CH2-CH2-O-CH2-CH2-C(O)-,-C(O)-CH2-CH2-O-CH2-CH2-NH-,-NH-(CH2) 4-C(O)-,-NH-(CH2)5-C(O)-,-NH-(CH2)6-C(O)-,-C(O)-(CH2)4-NH-,-C(O)-(CH2)5-NH-,-C(O)-(CH2)6-NH-,-NH-(CH2-CH2-O)-(CH2)3-,-NH-(CH2-CH2-O)-(CH2)4-,-NH-(CH2-CH2-O)-(CH2)5-,-NH-(CH2-CH2-O)-(CH2)6-,-(CH2)3-(O-CH2-CH2)-NH-,-(CH2)4-(O-CH2-CH2)-NH-,-(CH2)5-(O-C H2-CH2)-NH-,-(CH2)6-(O-CH2-CH2)-NH-,-CH2-CH2-O-(CH2)2-C(O)-,-CH2-CH2-O-(CH2)3-C(O)-,-CH2-CH2-O-(CH2)4-C(O)-,-C(O)-(CH2)2-O-CH 2-CH2-, -C(O)-(CH2)3-O-CH2-CH2-, -C(O)-(CH2)4-O-CH2-CH2-, -C(O)-(CH2)2-, -C(O)-(CH2)3-, -C(O)-(CH2)4-, -C(O)-(CH2)5-, -C(O)-(CH2)6--(CH2)2-C(O)-,-(CH2)3-C(O)-,-(CH2)4-C(O)-,-(CH2)5-C(O)-,-(CH2)6-C(O)-,-C(O)-(CH2)2-C(O)-,-C(O)-(CH2)3-C(O)-,-C(O)-(CH2)4-C(O)-,-C(O)-(CH2)5-C(O)-,-C(O)-(CH2)6-C(O)-,-CH2-C(O)-CH2-,-CH2- C(O)-(CH2)2-,-CH2-C(O)-(CH2)3-,-CH2-C(O)-(CH2)4-,-(CH2)2-C(O)-CH2-,-(CH2)2-C(O)-(CH2)2-,-(CH2)2-C(O)-(CH2)3-,-(CH2)2-C(O)-(CH2)4-,-(CH2)3-C(O)-CH2-,-(CH2)3-C(O)-(CH2)2-,-(CH2)3-C(O)-(CH2) 2)3-、-(CH2)3-C(O)-(CH2)4-、-(CH2)4-C(O)-CH2-、-(CH2)4-C(O)-(CH2)2-、-(CH2)4-C(O)-(CH2)3-、-(CH2)4-C(O)-(CH2)4-、-CH2-O-CH2-、-CH2-O-(CH2)2-、-CH2-O-(CH2)3-、-CH2-O-(CH2)4-、-(CH2)2-O-CH2-、-(CH2) 2-O-(CH2)2-,-(CH2)2-O-(CH2)3-,-(CH2)2-O-(CH2)4-,-(CH2)3-O-CH2-,-(CH2)3-O-(CH2)2-,-(CH2)3-O-(CH2)3-,-(CH2)3-O-(CH2)4-,-(CH2)4-O-CH2-,-(CH2)4-O-(CH2)2-,-(CH2)4-O-(CH2)3-,-(CH2)4-O-(CH2)4-, Preferably, the L is selected from the following structures: The compound represented by formula (Ⅱ-1): CLM1―L1―PTM1 (Ⅱ-1), Or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, in: PTM1 includes the structure shown in equation (Ⅲ-1): In formula (Ⅲ-1), R1 is selected from N, CF, C-Cl, C-Br and C (C1-C6 alkyl); R2 is selected from N, CH, CF, C-Cl, C-Br and C (C1-C6 alkyl); R3 is selected from C1-C3 alkyl, C1-C3 alkoxy, and halogen-substituted C1-C3 alkyl; R4 is selected from N, CH, CF, C-Cl, C-Br, C (C1-C6 alkyl) and C (C1-C6 alkoxy); R5 is selected from N and CH; R6 is selected from N, CH, CF, C-Cl, C-Br, C (C1-C6 alkyl) and C (C1-C6 alkoxy); R7 is selected from N and CH; R m8 Selected from hydrogen, halogens, and C1-C6 alkyl groups; R m9 Selected from hydrogen, halogens, and C1-C6 alkyl groups; R m10 Selected from hydrogen and C1-C6 alkyl groups; R m11 Selected from hydrogen and C1-C6 alkyl groups; CLM1 includes structures selected from the following: Among them, W 1 For C (=O), W 2 For CH2, or W 1 CH2, W 2 It is C (=O); W 5 and W 6 Each time it appears, it is independently CH2, CH(C1-C6 alkyl) or C(C1-C6 alkyl)2; R8 and R9 are each independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy and hydroxyl groups each time they appear; R 32 R 42 R 52 and R 62 Each time it appears, it is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy and cyano, more preferably H, F, Cl, Br, methyl, methoxy or cyano; R T Let N be the number of people in the group. R F and R G Each occurrence is independently selected from CH2, NH, O, and C(O); m3 is 2; m4 is 2; R 1D and R 1E Each occurrence is CH2; m7 is 0, m11 is 0, m12 is 1; or m7 is 2, m11 is 0, m12 is 0; L1 is L as defined in any one of claims 1-9, preferably, L1 is selected from... The compound of claim 11, wherein, R1 is selected from CF, C-Cl, C-Br and C (C1-C3 alkyl); preferably CF; and / or R2 is selected from N, CH, CF, and C-CH3, preferably CH; and / or R3 is selected from methyl, ethyl, methoxy, ethoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, or trifluoroethyl; preferably, R3 is difluoroethyl; preferably, R3 is CH2CHF2; and / or R4 is N, CH, CF, C-Cl, C-Br, or C-OCH3, preferably CF; and / or R5 is CH; and / or R6 is N, CH, CF, C-Cl, C-Br, or C-OCH3, preferably CF; and / or R7 is CH; and / or R m8 It is H, F, Cl, Br, I, or methyl, preferably hydrogen; and / or R m9 It is H, F, Cl, Br, I, or methyl, preferably hydrogen; and / or R m10 It is hydrogen and C1-C3 alkyl, preferably hydrogen; and / or R m11 Selected from hydrogen and C1-C6 alkyl groups, preferably hydrogen or methyl, more preferably methyl; and / or W 1 For C (=O), W 2 CH2; and / or W 5 CH2, W 6 CH2; and / or R8 is H, R9 is H; and / or R 32 R 42 R 52 and R 62 Each of the groups is independently selected from H, F, Cl, Br, methyl, methoxy, and cyano groups when it appears; preferably, R 32 R 42 R 52 and R 62 Each occurrence is independently H; and / or R T For N; and / or R F and R G For CH2; m3 is 2; m4 is 2; and / or R 1D and R 1E Each occurrence is CH2; m7 is 0, m11 is 0, m12 is 1; or m7 is 2, m11 is 0, m12 is 0. The compound shown in formula (IA), Or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, In the formula, X1 is N or CH; X2 is N or CH; X3 is N or CH; q1 is 0 or 1; q2 is 0, 1 or 2; R3 is selected from fluoroethyl, difluoroethyl and trifluoroethyl; R m9 Selected from hydrogen, halogens, and C1-C6 alkyl groups; R m10 Selected from hydrogen and C1-C6 alkyl groups; R m11 Selected from hydrogen, methyl, ethyl, and isopropyl; R4 is selected from N, CH, CF, C-Cl, C-Br, C (C1-C6 alkyl) and C (C1-C6 alkoxy); R5 is either N or CH; R6 is selected from N, CH, CF, C-Cl, C-Br, C(C1-C6 alkyl), and C(C1-C6 alkoxy). R7 is either N or CH; CLM includes structures selected from those shown in Equations (IV-1a), (IV-1b), and (IV-1c): Among them, W 1 For C (=O), W 2 For CH or W 1 For CH, W 2 For C (=O); preferably, W 1 For C (=O), W 2 For CH; R 32 R 42 R 52 and R 62 Each of the following groups is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, and cyano, preferably H, F, Cl, Br, methyl, methoxy, or cyano; R F R G Each occurrence is independently selected from CH2, NH, O, and C(O); CH2 is preferred; m3 is 2; m4 is 2; R 1D R 1E Each occurrence is CH; m7 is 0, m11 is 0, m12 is 1; or m7 is 2, m11 is 0, m12 is 0. A compound as shown in Formula II-AA, said compound having the following chemical structure: CLM―L―PTM(Formula II-AA), Or it may be its isomer, isotope derivative, polymorph, prodrug, or a pharmaceutically acceptable salt or solvate thereof. in: PTM targets the binding portion of the estrogen receptor protein and has the following structural formula III: R1 and R2 are each independently selected from N or CR. mm , R3 is selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally replaced by 1, 2, 3, 4, or 5 atoms, each independently selected from carboxyl, deuterium, halogen, etc. Substituents of the following groups: C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R3 is... R4 is selected from N or CRm4. R5 is selected from N or CRm5. R6 is selected from N or CRm6. R7 is selected from N or CRm7. R mm R m1 R m2 R m3 R m4 R m5 R m6 R m7 R m8 R m9 R m10 R m11 Each occurrence is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, C1-C6 alkylaminoacyl; preferably, R mm R m1 R m2 R m3 R m4 R m5 R m6 R m7 R m8 R m9 R m10 R m11 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R mm R m8 R m9 At least one is not H; preferably, R mm R m8 R m9 Each occurrence is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, with at least one not being H; preferably, R mm R m8 R m9 Each occurrence is independently H, C1-C3 alkyl, or F, and at least one is not H; preferably, R1 is N, C(CH3), or C(F); preferably, R1 is C(F); or or R m4 and R m5 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloyl group, C6-C 10 The aryl group is substituted with one or more substituents selected from 5-10 heteroaryl groups; preferably, R m4 and R m5 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 5-7 membered cycloalkyl group or a 5-7 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, wherein the saturated or unsaturated 5-7 membered cycloalkyl group or the 5-7 membered heterocycloalkyl group is unsubstituted or optionally substituted by one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, and amino; or R m6 and R m7 The carbon atom to which it is attached can form a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, C6-C 10 Aryl, C5-C 10 The substituent is a heteroaryl group and one or more substituents of a 5-10 member heteroaryl group; more preferably, R m6 and R m7 The carbon atom to which it is attached can form a saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocycloalkyl, wherein the saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocycloalkyl is unsubstituted or is optionally substituted by one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, and amino. When R1 and R2 are both CH, R m4 and R m5 And the atoms they are connected to form saturated or unsaturated ring structures, or, R m6 and R m7 The carbon atoms they are attached to form saturated or unsaturated ring structures; L is a bond that covalently connects the CLM and the PTM, or -(B L ) q -:B L Each occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, SO, SO2, NR L3 SO2NR L3 SONR L3 CONR L3 NR L3 CONR L4 NR L3 SO2NR L4 CO, CR L1 =CR L2 C≡C, SiR L1 R L2 P(O)R L1 P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 0-6 R groups. L1 and / or R L2 Group substitution; preferably, B L Each occurrence is independently selected from: CR L1 R L2 O, S, SO, SO2, NR L3 CO, C≡C, 3-16 cycloalkylene, 3-16 heterocyclic, 6-10 aryl, or 5-10 heteroaryl, wherein the 3-16 cycloalkylene, 3-16 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are optionally surrounded by 0, 1, 2, or 3 Rs. L1 and / or R L2 Group substitution; R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, C. 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, CO-C 3-8 cycloalkyl, CO-C 3-11 Heterocyclic, O-aryl, O-heteroaryl, SC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, N(C) 3-8 cycloalkyl)2, N(C) 3-8 cycloalkyl)(C 1-8 Alkyl), N(C) 1-8 Alkylene)(C 3-8 cycloalkyl), NH-C 3-8 Heterocyclic groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8 Heterocyclic group)(C 1-8 Alkyl), NH-aryl, N(aryl) (C 1-8 Alkyl), NH-heteroaryl, N(heteroaryl) (C 1-8 Alkyl), OH, NH2, SH, SO2P(O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, CO-C 1-8 Alkyl, COO-C 1-8 Alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C) 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C) 1-8 Alkyl)2, CONH-C 1-8 Alkyl, CONH-C 3-8 cycloalkyl, CONH-C 3-11 Heterocyclic groups, CON(C) 1-8 Alkyl)2, N(C) 1-8 Alkyl)CONH(C 1-8 Alkyl), N(C) 1-8 Alkyl)CON(C 1-8 Alkyl)2, NHCONH(C 1-8 Alkyl), NHCON (C 1-8 Alkyl)2, NHCONH2, N(C) 1-8 alkyl)SO2NH(C 1-8 Alkyl), N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 Alkyl), NH SO2N (C 1-8 Alkyl)2, and NH2SO2NH2, optionally, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic group, C 6-10 The aryl and 5-10 heteroaryl groups are each independently substituted by one or more substituents selected from halogens, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxyl, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl, and haloheteroaryl; preferably, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups are each independently selected from F, Cl, Br, I, C. 1-6 The substance is substituted by one or more substituents selected from alkyl, methoxy, and ethoxy groups; q is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; The CLM is the cerebellar protein E3 ubiquitin ligase-binding moiety, preferably, the CLM is selected from the following structures. W 1 and W 2 Each independently for CR a R b C (=O), NR a Or SO2, and W 1 and W 2 At least one of them is C (=O); G and Z are each independently selected from O, S, and Se; W5 and W6 each appear independently as C(R) m 2. NR m , O or S; W 11 For CR a R b C (=O), NR a Or SO2, R8, R9, R a R m R N and R b Each group, when appearing independently, is selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R8, R9, and R a R m R N and R b Each time it appears, it is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino. R 22 Selected from single bonds, CO, O, S, SO2, -NR m -、-NR m Combinations of one or more of CO-, alkylene, alkenylene, ynylene, haloalkylene, and heteroalkylene; n is 0, 1, 2, or 3; R 32 and R 42 The carbon atoms attached to it form And R 52 R 62 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substituent is one or more of the following: heterocyclic, aryl, and heteroaryl, preferably R. 52 R 62 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Each heteroaryl group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted, preferably R. 52 R 62 and R 72 Each is independently selected from H, deuterium, halogen, C1-C3 alkyl, and C1-C3 alkoxy; or R 42 and R 52 The carbon atoms attached to it form And R 32 R 62 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substituent is one or more of the following: heterocyclic, aryl, and heteroaryl, preferably R. 32 R 62 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Each heteroaryl group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted, preferably R. 32 R 62 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; or R 52 and R 62 The carbon atoms attached to it form And R 32 R 42 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substituent is one or more of the following: heterocyclic, aryl, and heteroaryl, preferably R. 32 R 42 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Each heteroaryl group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted, preferably R. 32 R 42 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; R d R e R f R g R D R E R F R G R f1 R g1 R F1 and R G1 Each occurrence is independently C(R) m 2. NR m O, C(O) or S; W 3 and W 4 Each independently for CR m Or N; R t R T R t1 R T1 Each independently for CR m Or N, R t R T R t1 R T1 Side connection Represents the connection site between CLM and L; m1 and m2 each appear independently as integers of 0, 1, 2, 3, 4, 5 or 6, and m1 + m2 ≤ 6; m3 appears as an integer of 0, 1, 2, 3, 4, 5, 6 or 7 each time, and m4 appears as an integer of 1, 2, 3, 4, 5, 6, 7 or 8 each time, and m3 + m4 ≤ 8; m5 and m6 each appear independently as integers of 0, 1, 2, 3, 4, 5, 6 or 7, and m5 + m6 ≤ 7; m7 and m8 each appear independently as integers of 0, 1, 2, 3, 4, 5, 6 or 7, and m7 + m8 ≤ 7; m31 is an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m41 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8, and m31 + m41 ≤ 8; and m51 is an integer of 0, 1, 2, 3, 4, 5, 6 or 7, m61 is an integer of 1, 2, 3, 4, 5, 6, 7 or 8, and m51 + m61 ≤ 8. The compound of claim 14, wherein, When R1 and R2 in equation III are not both CH, the equation in equation III... Selected from unsubstituted or substituted with one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino. When R1 and R2 in equation III are both CH, in equation III Selected from unsubstituted or substituted with one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino. A compound as shown in Formula II, said compound having the following chemical structure: CLM―L―PTM(Formula II), Or it may be its isomer, isotope derivative, polymorph, prodrug, or a pharmaceutically acceptable salt or solvate thereof. in: PTM targets the binding portion of the estrogen receptor protein and has the following structural formula III: R1 and R2 are each independently selected from N or CR. mm , R3 is selected from H, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally replaced by 1, 2, 3, 4, or 5 atoms, each independently selected from carboxyl, deuterium, halogen, etc. Substituents of the following groups: C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R3 is... R4 is selected from N or CRm4. R5 is selected from N or CRm5. R6 is selected from N or CRm6. R7 is selected from N or CRm7. R mm R m1 R m2 R m3 R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R mm R m1 R m2 R m3 R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino, and R mm R m8 and R m9 Each occurrence must contain at least one non-H; more preferably, R mm R m1 R m2 R m3 R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino, and R mm and R m9 Each occurrence must contain at least one non-H; more preferably, R mm R m1 R m2 R m3 R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently selected from H, F, Cl, Br, I, C1-C6 alkyl groups and R mm R m8 and R m9 Each occurrence must have at least one element that is not H; more preferably, R mm R m1 R m2 R m3 R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently selected from H, F, Cl, Br, I, C1-C6 alkyl groups and R mm R m8 and R m9 Each occurrence must have at least one element that is not H; preferably, R mm R m1 R m2 R m3 R m4 R m5 R m6 R m7 R m8 R m9 R m10 and R m11 Each occurrence is independently of H, C1-C3 alkyl, F, Cl, Br, and I, and R mm R m8 and R m9 Each occurrence must have at least one element that is not H; preferably, R mm R m8 and R m9 Each occurrence is independently selected from H, F, Cl, Br, I, and C1-C6 alkyl groups, with at least one not being H; preferably, R mm R m8 and R m9 Each occurrence is independently of H, C1-C3 alkyl, F, Cl, Br, and I, and R mm and R m9 Each occurrence must have at least one element that is not H; or R m4 and R m5 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloyl group, C6-C 10 The aryl group is substituted with one or more substituents selected from 5-10 heteroaryl groups; preferably, R m4 and R m5 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 5-7 membered cycloalkyl group or a 5-7 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the saturated or unsaturated 5-7 membered cycloalkyl group or the 5-7 membered heterocycloalkyl group is unsubstituted or optionally substituted by one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, and amino; or R m6 and R m7 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, C6-C 10 Aryl, C5-C 10 The substituent is a heteroaryl group and one or more substituents of a 5-10 member heteroaryl group; more preferably, R m6 and R m7 The carbon atom to which it is attached can form a saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocycloalkyl, wherein the saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocycloalkyl is unsubstituted or is optionally substituted by one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino. When both R1 and R2 are CH, R m9 When it is H, R m4 and R m5 And the atoms they are connected to form saturated or unsaturated ring structures, or, R m6 and R m7 The carbon atoms to which it is attached form a saturated or unsaturated ring structure, or one of R4 and R6 is selected from N; or R mm R m8 and R m9 At least one of them is not H in each occurrence; Preferably, R mm and R m9 At least one of them is not H in each occurrence; L is a bond that covalently connects the CLM and the PTM, or -(B L ) q -:B L Each occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, SO, SO2, NR L3 SO2NR L3 SONR L3 CONR L3 NR L3 CONR L4 NR L3 SO2NR L4 CO, CR L1 =CR L2 C≡C, SiR L1 R L2 P(O)R L1 P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 Cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 0-6 R groups. L1 and / or R L2 Group substitution; preferably, B L Each occurrence is independently selected from: CR L1 R L2 O, S, SO, SO2, NR L3 CO, C≡C, 3-16 cycloalkylene, 3-16 heterocyclic, 6-10 aryl, or 5-10 heteroaryl, wherein the 3-16 cycloalkylene, 3-16 heterocyclic, 6-10 aryl, or 5-10 heteroaryl are optionally surrounded by 0, 1, 2, or 3 Rs. L1 and / or R L2 Group substitution; R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, C. 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, aryl, heteroaryl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, CO-C 3-8 cycloalkyl, CO-C 3-11 Heterocyclic, O-aryl, O-heteroaryl, SC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, N(C) 3-8 cycloalkyl)2, N(C) 3-8 cycloalkyl)(C 1-8 Alkyl), N(C) 1-8 Alkylene)(C 3-8 cycloalkyl), NH-C 3-8 Heterocyclic groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8 Heterocyclic group)(C 1-8 Alkyl), NH-aryl, N(aryl) (C 1-8 Alkyl), NH-heteroaryl, N(heteroaryl) (C 1-8 Alkyl), OH, NH2, SH, SO2P(O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, CO-C 1-8 Alkyl, COO-C 1-8 Alkyl, CO2H, CN, CF3, CHF2, CH2F, NO2, SF5, SO2NH-C 1-8 Alkyl, SO2N(C) 1-8 Alkyl)2, SONH-C 1-8 Alkyl, SON(C) 1-8 Alkyl)2, CONH-C 1-8 Alkyl, CONH-C 3-8 cycloalkyl, CONH-C 3-11 Heterocyclic groups, CON(C) 1-8 Alkyl)2, N(C) 1-8 Alkyl)CONH(C 1-8 Alkyl), N(C) 1-8 Alkyl)CON(C 1-8 Alkyl)2, NHCONH(C 1-8 Alkyl), NHCON (C 1-8 Alkyl)2, NHCONH2, N(C) 1-8 alkyl)SO2NH(C 1-8 Alkyl), N(C) 1-8 Alkyl)SO2N(C 1-8 Alkyl)2, NHSO2NH(C 1-8 Alkyl), NH SO2N (C 1-8 Alkyl)2, and NH2SO2NH2, optionally, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic group, C 6-10 The aryl and 5-10 heteroaryl groups are each independently substituted by one or more substituents selected from halogens, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxyl, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl, and haloheteroaryl; preferably, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups are each independently selected from F, Cl, Br, I, C. 1-6 The substance is substituted by one or more substituents selected from alkyl, methoxy, and ethoxy groups; q is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; The CLM is the cerebellar protein E3 ubiquitin ligase-binding moiety, preferably, the CLM is selected from the following structures. W 1 and W 2 Each independently for CR a R b C (=O), NR a Or SO2, and W 1 and W 2 At least one of them is C (=O); G and Z are each independently selected from O, S, and Se; W5 and W6 each appear independently as C(R) m 2. NR m , O or S; W 11 For CR a R b C (=O), NR a Or SO2, R8, R9, R a R m R N and R b Each group, when appearing independently, is selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R8, R9, R a R m R N and R b Each time it appears, it is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino. R 22 Selected from single bonds, CO, O, S, SO2, -NR m -、-NR m Combinations of one or more of CO-, alkylene, alkenylene, ynylene, haloalkylene, and heteroalkylene; n is 0, 1, 2, or 3; R 32 and R 42 The carbon atoms attached to it form And R 52 R 62 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C2-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substituent is one or more of the following: heterocyclic, aryl, and heteroaryl, preferably R. 52 R 62 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Each heteroaryl group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted, preferably R. 52 R 62 and R 72 Each is independently selected from H, deuterium, halogen, C1-C3 alkyl, and C1-C3 alkoxy; or R 42 and R 52 The carbon atoms attached to it form And R 32 R 62 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C2-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substituent is one or more of the following: heterocyclic, aryl, and heteroaryl, preferably R. 32 R 62 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Each heteroaryl group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted, preferably R. 32 R 62 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; or R 52 and R 62 The carbon atoms attached to it form And R 32 R 42 and R 72 Each is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C2-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substituent is one or more of the following: heterocyclic, aryl, and heteroaryl, preferably R. 32 R 42 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Each heteroaryl group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 One or more substituents in the heteroaryl group are substituted, preferably R. 32 R 42 and R 72 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C3 alkyl, and C1-C3 alkoxy; R d R e R f R g R D R E R F R G R f1 R g1 R F1 and R G1 Each occurrence is independently C(R) m 2. NR m O, C(O) or S; W 3 and W 4 Each independently for CR m Or N; R t R T R t1 R T1 Each independently for CR m Or N, R t R T R t1 R T1 Side connection Represents the connection site between CLM and L; m1 and m2 each appear independently as integers of 0, 1, 2, 3, 4, 5 or 6, and m1 + m2 ≤ 6; m3 appears as an integer of 0, 1, 2, 3, 4, 5, 6 or 7 each time, and m4 appears as an integer of 1, 2, 3, 4, 5, 6, 7 or 8 each time, and m3 + m4 ≤ 8; m5 and m6 each appear independently as integers of 0, 1, 2, 3, 4, 5, 6 or 7, and m5 + m6 ≤ 7; m7 and m8 each appear independently as integers of 0, 1, 2, 3, 4, 5, 6 or 7, and m7 + m8 ≤ 7; m31 is an integer of 0, 1, 2, 3, 4, 5, 6, or 7, and m41 is an integer of 1, 2, 3, 4, 5, 6, 7, or 8, and m31 + m41 ≤ 8; and m51 is an integer of 0, 1, 2, 3, 4, 5, 6 or 7, m61 is an integer of 1, 2, 3, 4, 5, 6, 7 or 8, and m51 + m61 ≤ 8. The compound of claim 16, wherein, When R1, R2 and R in equation III m9 When they are not simultaneously CH, CH, and H, the values ​​in Equation III are... Selected from unsubstituted or substituted by one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino. When R1 and R2 in equation III are both CH, and R m9 When H is used, in equation III Selected from unsubstituted or substituted by one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino. The compound as described in claim 1 or any one of claims 14-17 is selected from: Compounds containing the structure shown in formula (Ⅰ') that bind estrogen receptor proteins: Or its pharmaceutically acceptable salt; In the formula, R ER0’ It is a leaving group; R1, R2, R3, R4, R5, R6, R7, R m8 R m9 R m10 and R m11 Each custom definition is identical to any one of claims 1-3; R ER0’ Selected from -(CR) ERa R ERb ) n1 R ERc Methanesulfonate group (Ms), trifluoromethanesulfonate group (Tf), p-toluenesulfonyl chloride group (TsCl), p-benzenemethylsulfonate group (Ts), -C(O)OR ERd and -OC(O)R ERd ; R ERa R ERb R ERc and R ERd Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, hydroxyl, nitro, cyano, amino and -ON=NH, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl are optionally substituted by one or more substituents independently selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, carboxyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and amino; n1 is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; Preferably, R ER0’ Selected from Cl, Br, I, methoxy, hydroxy, nitro, amino, -OC(O)CH3, -ON=NH, OTf, O-Br, Ms, Tf, Ts, TsCl, C(O)OCH3, C(O)OCH3, CH2NO2, CH2ON=NH and CH2NH2; Preferably, Selected from More preferably and / or Selected from in, When R1, R2 and R in equation III m9 When they are not simultaneously CH, CH, and H, the values ​​in Equation III are... Selected from unsubstituted or substituted by one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino. When R1 and R2 in equation III are both CH, and R m9 When H is used, in equation III Selected from unsubstituted or substituted by one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino. Preferably, when Selected from hour, Selected from when for hour, Selected from A compound that binds to an estrogen receptor protein, having the structure shown in Formula I-B: in, R ER0 Selected from -(CR) ERa R ERb ) n1 R ERc Methanesulfonate group (Ms), trifluoromethanesulfonate group (Tf), p-toluenesulfonyl chloride group (TsCl), p-benzenemethylsulfonate group (Ts), -C(O)OR ERd and -OC(O)R ERd ; R ERa R ERb R ERc and R ERd Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, hydroxyl, nitro, cyano, amino, and -ON=NH. The C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl are optionally substituted by one or more substituents independently selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 alkoxy, hydroxyl, carboxyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, and amino. n1 is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; R ER1 and R ER2 Each is independently selected from N or CR ERm ; R ER3 -N(R) ERm31 )-; R ERm31 The group is selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally surrounded by 1, 2, 3, 4, or 5 atoms, each independently selected from carboxyl, deuterium, halogen, etc. Substituents of the following groups: C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R ERm31 for R ER4 Selected from -N- and -C(R) ERm4 )-; R ER5 Selected from -N- and -C(R) ERm5 )-; R ER6 Selected from -N- and -C(R) ERm6 )-; R ER7 Selected from -N- and -C(R) ERm7 )-;and R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 R ERm6 R ERm7 R ER8 R ER9 R ER10 and R ER11 Each group, when appearing independently, is selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 R ERm6 R ERm7 R ER8 R ER9 R ER10 and R ER11 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; preferably, R ERm R ERm8 R ERm9 At least one of them is not H; or R ERm4 and R ERm5 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S. The saturated or unsaturated 4-10 membered cycloalkyl group or 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloyl group, C6-C 10 The aryl group is substituted with one or more substituents selected from 5-10 heteroaryl groups; preferably, R ERm4 and R ERm5 The atom to which it is attached is capable of forming a saturated or unsaturated 5-7 membered cycloalkyl group or a 5-7 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the saturated or unsaturated 5-7 membered cycloalkyl group or the 5-7 membered heterocycloalkyl group is unsubstituted or optionally substituted with one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, and amino; or R ERm6 and R ERm7 The carbon atom to which it is attached can form a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, C6-C 10 Aryl, C5-C 10 The substituent is a heteroaryl group and one or more substituents of a 5-10 member heteroaryl group; preferably, R ERm6 and R ERm7 The carbon atom to which it is attached can form a saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocycloalkyl, wherein the saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocycloalkyl is unsubstituted or is optionally substituted by one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, and amino. And when R ER1 R ER2 When both are CH, R ERm4 and R ERm5 The atoms to which they are attached form saturated or unsaturated ring structures; or, R ERm6 and R ERm7 The atoms they are connected to form saturated or unsaturated ring structures. The compound of claim 20, wherein, When R ER1 R ER2 When they are not both CH, in Equation I Selected from unsubstituted or substituted with one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, and amino. When R ER1 R ER2 When both are CH, in equation I Selected from unsubstituted or substituted with one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, and amino. A compound that binds to an estrogen receptor protein, having the structure shown in Formula I: in, R ER0 Selected from -(CR) ERa R ERb ) n1 R ERc Methanesulfonate group (Ms), trifluoromethanesulfonate group (Tf), p-toluenesulfonyl chloride group (TsCl), p-benzenemethylsulfonate group (Ts), -C(O)OR ERd and -OC(O)R ERd ; R ERa R ERb R ERc and R ERd Each of the following groups is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, hydroxyl, nitro, cyano, amino and -ON=NH, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, 3-10 membered cycloalkyl and 3-10 membered heterocycloalkyl are optionally substituted by one or more substituents independently selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, carboxyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl and amino; n1 is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; R ER1 and R ER2 Each is independently selected from N or CR ERm ; R ER3 -N(R) ERm31 )-; R ERm31 The group is selected from H, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally surrounded by 1, 2, 3, 4, or 5 atoms, each independently selected from carboxyl, deuterium, halogen, etc. Substituents of the following groups: C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R ERm31 for R ER4 Selected from -N- and -C(R) ERm4 )-; R ER5 Selected from -N- and -C(R) ERm5 )-; R ER6 Selected from -N- and -C(R) ERm6 )-; R ER7 Selected from -N- and -C(R) ERm7 )-; R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 R ERm6 R ERm7 R ER8 R ER9 R ER10 and R ER11 Each group, when appearing independently, is selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R ERm R ERm1 R ERm2 R ERm3 R ERm4 R ERm5 R ERm6 R ERm7 R ER8 R ER9 R ER10 and R ER11 Each is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; or R ERm4 and R ERm5 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S. The saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloyl group, C6-C 10 The aryl group is substituted with one or more substituents selected from 5-10 heteroaryl groups; preferably, R ERm4 and R ERm5 The atom to which it is attached is capable of forming a saturated or unsaturated 5-7 membered cycloalkyl group or a 5-7 membered heterocycloalkyl group containing 1-3 heteroatoms, each independently selected from N, O, and S, wherein the saturated or unsaturated 5-7 membered cycloalkyl group or the 5-7 membered heterocycloalkyl group is unsubstituted or optionally substituted with one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, and amino; or R ERm6 and R ERm7 The carbon atom to which it is attached is capable of forming a saturated or unsaturated 4-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, wherein the saturated or unsaturated 4-10 membered cycloalkyl group or the 4-10 membered heterocycloalkyl group is unsubstituted or optionally selected from F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocycloalkyl group containing 1-3 heteroatoms each independently selected from N, O, and S, C6-C 10 Aryl, C5-C 10 The substituent is a heteroaryl group and one or more substituents of a 5-10 member heteroaryl group; preferably, R ERm6 and R ERm7 The carbon atom to which it is attached can form a saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocycloalkyl, wherein the saturated or unsaturated 5-7 membered cycloalkyl or 5-7 membered heterocycloalkyl is unsubstituted or is optionally substituted by one or more substituents selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino. And when R ER1 R ER2 Both are CH, and R ER9 When it is H, R ERm4 and R ERm5 The atoms to which they are attached form saturated or unsaturated ring structures; or, R ERm6 and R ERm7 And the atoms they are connected to form saturated or unsaturated ring structures, or R ER4 and R ER5 One of them is selected from N; or R mm R m8 and R m9 At least one of them is not H in each occurrence; Preferably, R mm and R m9 Each occurrence must have at least one value that is not H. The compound of claim 22, wherein, When R ER1 R ER2、 and R ER9 When they are not simultaneously CH, CH and H, respectively, in Equation I Selected from unsubstituted or substituted with one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino. When R ER1 R ER2 Both are CH, and R ER9 When H is , when, in Equation I Selected from unsubstituted or substituted with one or more substituents selected from deuterium, F, Cl, Br, I, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino. The compound according to any one of claims 19-23 is selected from: The compound represented by formula (Ⅳ'): CLM―L―A L2 (Ⅳ') Or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, In the formula, CLM and L are defined as in any one of claims 1-2 and 7-10; A L2 Independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups, wherein the C1-C6 alkyl, C2-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic, aryl, and heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C2-C6 heteroalkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, and C4-C6 cycloalkyl groups. 10 The substance is substituted by one or more substituents of heterocyclic, aryl, and heteroaryl groups; Preferably, A L2 Selected from The compound of claim 25, wherein the compound is selected from the following structures: Use of any compound of any one of claims 19-26 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for degrading estrogen receptor proteins. A pharmaceutical composition comprising a compound as described in any one of claims 1-18 and at least one pharmaceutically acceptable carrier. The use of the compound of any one of claims 1-18 or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, or the pharmaceutical composition of claim 28 in the preparation of a medicament for treating or preventing a disease; wherein the disease is a disease treated by degrading estrogen receptor proteins or a disease associated with the accumulation and / or aggregation of estrogen receptor proteins. The use as described in claim 29, wherein the disease is cancer, preferably breast cancer, ductal carcinoma of the breast, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myeloid monocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer; preferably, the breast cancer is ER. + Breast cancer; preferably, the breast cancer has a Y537S or D538G mutation. A method of treating or preventing a disease, comprising administering to a subject in need a therapeutically effective amount of the compound of any one of claims 1-18 or an isomer thereof, isotopic derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate, or the pharmaceutical composition of claim 28; wherein the disease is a disease treated by degrading estrogen receptor proteins or a disease associated with the accumulation and / or aggregation of estrogen receptor proteins. The method of claim 31, wherein the disease is cancer, preferably breast cancer, ductal carcinoma of the breast, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myeloid monocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer; preferably, the breast cancer is ER+ breast cancer; preferably, the breast cancer has a Y537S or D538G mutation. The compound of any one of claims 1-18 or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, or the pharmaceutical composition of claim 28, for the treatment or prevention of a disease; wherein the disease is a disease treated by degrading estrogen receptor proteins or a disease associated with the accumulation and / or aggregation of estrogen receptor proteins. The compound of claim 33 or its isomers, isotope derivatives, polymorphs, prodrugs, pharmaceutically acceptable salts or solvates, or the pharmaceutical composition thereof, wherein the disease is cancer, preferably breast cancer, ductal carcinoma of the breast, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myeloid monocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, and / or cervical cancer; preferably, the breast cancer is ER + Breast cancer, preferably, the breast cancer has a Y537S or D538G mutation. A compound represented by formula IA, the compound having the following structure: CLM―La (Formula IA) Or it may be its isomer, isotope derivative, polymorph, prodrug, pharmaceutically acceptable salt or solvate. in: CLM is selected from the following structures: W 1 and W 2 Whether they are the same or different, each is independently a CR. a R b Or C(O), and W 1 and W 2 At least one of them is C(O); W 5 and W 6 Each occurrence is independently C(R) m )2; R 1D R 1E R F and R G Each occurrence is independently C(R) m 2. NR m C(O), O or S; R T For N or CR 2h ; Z is CR a Or N; R 32 R 42 R 62 R m and R 2h Each of the following groups is independently selected from H, deuterium, halogen, alkyl, deuterated alkyl, heteroalkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, alkylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, heteroalkyl, alkenyl, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are each independently and optionally substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, alkenyl, alkynylamino, alkylacyl, alkyloxyacyl, alkylaminoacyl, aryl, and heteroaryl; preferably, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, deuterium atom, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl and 5-10-membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, 4-10-membered heterocyclic, C6-C 10 The aryl and 5-10-membered heteroaryl groups are each independently selected from halogens, C1-C6 alkyl groups, C1-C6 heteroalkyl groups, C1-C6 alkoxy groups, halogenated C1-C6 alkyl groups, hydroxyl groups, C1-C6 hydroxyalkyl groups, cyano groups, amino groups, nitro groups, C3-C8 cycloalkyl groups, 4-10-membered heterocyclic groups, and C6-C6 heterocyclic groups. 10 The aryl group is substituted with one or more substituents selected from 5-10 heteroaryl groups; preferably, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, amino, C3-C8 cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 heteroaryl, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C8 cycloalkyl, C4-C 10 Heterocyclic group, C6-C 10 Aryl and C5-C 10 Each heteroaryl group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxyl, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocyclic, C6-C 10 The aryl group is substituted with one or more substituents of 5-10 heteroaryl groups; more preferably, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, deuterated C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo-C1-C6 alkyl, halo-C1-C6 alkoxy, and hydroxyl; more preferably, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C3 alkyl, deuterated C1-C3 alkyl, C1-C3 alkoxy, halo-C1-C3 alkyl, halo-C1-C3 alkoxy, and hydroxyl; more preferably, R 32 R 42 R 62 R 2h and R m Each occurrence is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, hydroxyl, and C1-C3 alkoxy; more preferably, R 32 R 42 R 62 R 2h and R m Each time it appears, it is independently selected from H, F, Cl, Br, I, C1-C3 alkyl and C1-C3 alkoxy groups; Each time m7, m11, and m12 appear, they are each an independent integer of 0, 1, 2, 3, 4, 5, or 6, and m7 + m11 + m12 ≤ 6; m3 and m4 each appear independently as integers of 0, 1, 2, 3 or 4; m3 and m4 are not both 0; m3 + m4 ≤ 5; R8 is selected from H, halogens, deuterium atoms, C1-C6 alkyl groups, C1-C6 alkoxy groups, hydroxyl groups, cycloalkyl groups, C1-C6 haloalkyl groups, and hydroxyalkyl groups; preferably, R8 is selected from H, halogens, deuterium atoms, C1-C3 alkyl groups, and hydroxyl groups; more preferably, R8 is selected from H, deuterium atoms, F, Cl, Br, I, C1-C3 alkyl groups, and hydroxyl groups; R9, R a and R b Each is independently selected from H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, and C1-C6 alkoxy; La is -(B L ) q -A L2 ; B L Each occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, S(O), S(O)2, NR L3 S(O)2NR L3 S(O)NR L3 C(O)NR L3 NR L3 C(O)NR L4 NR L3 S(O)2NR L4 C(O), CR L1 =CR L2 C≡C, SiR L1 R L2 P(O)R L1 P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 Monocyclic alkyl groups, monoheterocyclic alkyl groups, bridged cycloyl groups, and spirocyclic cycloyl groups, wherein the monocyclic alkyl groups, monoheterocyclic alkyl groups, bridged cycloyl groups, and spirocyclic cycloyl groups are optionally surrounded by 0, 1, 2, 3, 4, 5, or 6 R groups. L1 and / or R L2 Group substitution; preferably, B L Each occurrence is independently selected from: CR L1 R L2 O, S, SO, SO2, NR L3 C(O), C≡C, 3-8 membered monocyclic alkylene, 3-8 membered monocyclic heterocyclic group containing 1-3 heteroatoms independently selected from N, O and S, 5-15 membered bridged cyclic group containing 0-5 heteroatoms independently selected from N, O and S, and 5-15 membered spirocyclic group containing 0-5 heteroatoms independently selected from N, O and S, wherein the 3-8 membered monocyclic alkylene, 3-8 membered monocyclic heterocyclic alkylene, 5-15 membered bridged cyclic group and 5-15 membered spirocyclic group are optionally separated by 0, 1, 2 or 3 R L1 and / or R L2 Group substitution; R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, and C. 1-8 Alkyl, C 1-8 Alkoxy, -OC 1-8 Alkyl, -SC 1-8 Alkyl, -NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-1 1 heterocyclic group, C(O)-C 3-8 Cycloalkyl, C(O)-C 3-11 Heterocyclic groups, SC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, N(C) 3-8 cycloalkyl)2, N(C) 3-8 cycloalkyl)(C 1-8 Alkyl), N(C) 1-8 Alkylene)(C 3-8 cycloalkyl), NH-C 3-8 Heterocyclic groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8 Heterocyclic group)(C 1-8 Alkyl groups, -OH groups, -NH2 groups, -SH groups, S(O)2P(O) (OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl group, -C≡CH, CH=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, C(O)-C 1-8 Alkyl, C(O)-OC 1-8 Alkyl, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, S(O)2NH-C 1-8 Alkyl, S(O)2N(C) 1-8 Alkyl)2、S(O)NH-C 1-8 Alkyl, S(O)N(C) 1-8 Alkyl)2、C(O)NH-C 1-8 Alkyl, C(O)NH-C 3-8 cycloalkyl, C(O)NH-C 3-11 Heterocyclic groups, C(O)N(C) 1-8 Alkyl)2, N(C) 1-8 alkyl)C(O)NH(C 1-8 Alkyl), N(C) 1-8 alkyl)C(O)N(C 1-8 Alkyl)2、NHC(O)NH(C 1-8 Alkyl), NHC(O)N(C 1-8 Alkyl)2, NHC(O)NH2, N(C) 1-8 alkyl)S(O)2NH(C 1-8 Alkyl), N(C) 1-8 alkyl)S(O)2N(C 1-8 Alkyl)2, NHS(O)2NH(C 1-8 Alkyl), NHS(O)2N(C 1-8 Alkyl)2 and NHS(O)2NH2, optionally, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic groups and C 3-8 Each heterocyclic group is independently substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, halocycloalkyl, haloheteroalkyl and alkylamino; q is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; and A L2 Independently selected from H, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C3-C8 cycloalkyl, and C4-C 10 Heterocyclic groups, wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C8 cycloalkyl, and C4-C 10 Each heterocyclic group is independently selected from F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, and C4-C 10 One or more substituents in the heterocyclic group are substituted; And when -(B L ) q -A L2 When the carbon chain structure does not contain rings, q is an integer of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; When -(B) L ) q -A L2 When a monocyclic structure is contained, and the number of monocyclic structures is 1, the monocyclic structure is a C3-C8 heterocyclic alkyl group containing 1-3 N atoms; -(B L ) q -A L2 It is not H, -CH3, or -C(O)-CH3. The compound of claim 35, wherein, W 1 and W 2 Each independently for CR a R b And W 1 and W 2 At least one of them is C (=O); and / or W 5 and W 6 Each occurrence is independently C(R) m )2; and / or R 1D and R 1E Each occurrence is independently selected from C(R) m 2. NR m O and CO; and / or R F and R G Each occurrence is independently selected from C(R) m )2; and / or R T For N; and / or Z is CH or N; and / or R8, R9, R 32 R 42 R 62 R a R b and R m Each occurrence is independently selected from H, F, Cl, Br, I, C1-C3 alkyl, C1-C3 alkoxy, and hydroxyl; and / or Each occurrence of m7, m11, and m12 is an independent integer of 0, 1, 2, 3, 4, 5, or 6, and m7 + m11 + m12 ≤ 6; preferably, each occurrence of m7, m11, and m12 is an independent integer of 0, 1, 2, or 3, and m7 + m11 + m12 ≤ 3, preferably m7 + m11 + m12 = 2 or m7 + m11 + m12 = 1; and / or Each time m3 and m4 appear, they are each an independent integer of 0, 1, 2, 3, or 4; m3 and m4 are not both 0; and m3+m4=4, m3+m4=3, or m3+m4=2. The compound as described in claim 35 or 36, wherein, The CLM is selected from: The compound according to any one of claims 35-37, wherein, B L Selected from one or more of the following structures: -O-, -S-, -SO-, -SO2-, -CH2-, -CO-, -NH-, -C≡C-, -CH(CH3)-, -CH(CH2CH3)-, -C(CH3)2-, -N(CH3)-, -N(CH2CH3)-, This is the connection point. The compound of claim 38, wherein, -(B L ) q -Selected from the following structures: Covalent bond, -(CH2) j -, -(CH2) p -NH-(CH2) s -, -(CH2) y -NH-(CH2) j -NH-(CH2) s -, -(CH2) p -CO-(CH2) s -, -(CH2) p -O-(CH2) s -, -(CH2) y -CO-(CH2) j -CO-(CH2) s -, -(CH2) y -O-(CH2) j -O-(CH2) s -, -(CH2) y -O-(CH2) j -CO-(CH2) s -, -(CH2) p -NH-(CH2) y -O-(CH2) j -CO-(CH2) s -, Each time j appears, it is independently 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; k, s, p, and y are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and For connection points with CLM or PTM; Preferably, -(B L ) q - Selected from covalent bonds, -(CH2)2-OCH2CH2-, -(CH2)2-(OCH2CH2)2-, -(CH2)2-(OCH2CH2)3-, -(CH2)2-(OCH2CH2)4, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -NH-(CH2)9-, -NH-(CH2) 10 -、-NH-(CH2) 11 -、-NH-(CH2) 12 -、-NH-(CH2) 13 -、-NH-(CH2) 14 -、-NH-(CH2) 15 -NH-CH2-,-NH-(CH2)2-,-NH-(CH2)3-,-NH-(CH2)4-,-NH-(CH2)5-,-NH-(CH2)6-,-NH-(CH2)7-,-NH-(CH2)8-,-C(O)-NH-CH2-,-C(O)-NH-(CH2)2-,-C(O)-NH-(CH2)3-,-C(O)-NH-(CH2)4-,-(CH2)4-C(O)-NH-(CH2)4-,-(CH2)2-C(O)-NH-(CH2)3-,-(CH2)5-C(O)-NH-(CH2)8-,-C(O)-NH-(CH2) 2)5-,-C(O)-NH-(CH2)6-,-C(O)-NH-(CH2)7-,-C(O)-NH-(CH2)8-,-CH2-NH-,-(CH2)2-NH-,-(CH2)3-NH-,-(CH2)4-NH-,-(CH2)5-NH-,-(CH2)6-NH-,-(CH2)7-NH-,-(CH2)8-NH-,-NH-CH2-NH-,-NH-(CH2)2-NH-,-NH-(CH2)3-NH-,-NH-(CH2)4-NH-,-NH-(CH2)5-NH-,-NH-(CH2)6-NH-,-NH-(CH2 )7-NH-,-NH-(CH2)8-NH-,-(CH2-CH2-O)-CH2-CH2-,-(CH2-CH2-O)2-CH2-CH2-,-(CH2-CH2-O)3-CH2-CH2-,-NH-(CH2-CH2-O)-CH2-CH2-,-NH-(CH2-CH2-O)2-CH2-CH2-,-NH-(CH2-CH2-O)3-CH2-CH2-,-C(O)-NH-(CH2-CH2-O)-CH2-CH2-,-C(O)-NH-(CH2-CH2-O)2-CH2-CH2-,-C(O)-NH-(CH2-CH 2-O)3-CH2-CH2-、-(CH2-CH2-O)-CH2-CH2-NH-、-(CH2-CH2-O)2-CH2-CH2-NH-、-(CH2-CH2-O)3-CH2-CH2-NH-、-NH-(CH2-CH2-O)-CH2-CH2-NH-、-NH-(CH2-CH2-O)2-CH2-CH2-NH-、-NH-(CH2-CH2-O)3-CH2-CH2-NH-、-C(O)-NH-(CH2-CH2-O)-CH2-CH2-NH-、-C(O)-NH-(CH2-CH2-O)2-CH2-CH2-NH-、-C(O)-NH-(CH2-CH2-O)3-CH2-CH2-NH-、-CH2-CH2-(O-CH2-CH2)-、-CH2-CH2-(O-CH2-CH2)2-、-CH2-CH2-(O-CH2-CH2)3-、-NH-CH2-CH2-(O-CH2-CH2)-、-NH-CH2-CH2-(O-CH2-CH2)2-、-NH-CH2-CH2-(O-CH2-CH2)3-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)-、-C(O)-NH-CH2-CH2-(O-CH2-CH2)2-、-C(O)-NH- CH2-CH2-(O-CH2-CH2)3-,-CH2-CH2-(O-CH2-CH2)-NH-,-CH2-CH2-(O-CH2-CH2)2-NH-,-CH2-CH2-(O-CH2-CH2)3-NH-,-NH-CH2-CH2-(O-CH2-CH2)-NH-,-NH-CH2-CH2-(O-CH2-CH2)2-NH-,-NH-CH2-CH2-(O-CH2-CH2)3-NH-,-NH-CH2-CH2-O-CH2-CH2-C(O)-,-C(O)-CH2-CH2-O-CH2-CH2-NH-,-NH-(CH2) 4-C(O)-,-NH-(CH2)5-C(O)-,-NH-(CH2)6-C(O)-,-C(O)-(CH2)4-NH-,-C(O)-(CH2)5-NH-,-C(O)-(CH2)6-NH-,-NH-(CH2-CH2-O)-(CH2)3-,-NH-(CH2-CH2-O)-(CH2)4-,-NH-(CH2-CH2-O)-(CH2)5-,-NH-(CH2-CH2-O)-(CH2)6-,-(CH2)3-(O-CH2-CH2)-NH-,-(CH2)4-(O-CH2-CH2)-NH-,-(CH2)5-(O-C H2-CH2)-NH-,-(CH2)6-(O-CH2-CH2)-NH-,-CH2-CH2-O-(CH2)2-C(O)-,-CH2-CH2-O-(CH2)3-C(O)-,-CH2-CH2-O-(CH2)4-C(O)-,-C(O)-(CH2)2-O-CH 2-CH2-, -C(O)-(CH2)3-O-CH2-CH2-, -C(O)-(CH2)4-O-CH2-CH2-, -C(O)-(CH2)2-, -C(O)-(CH2)3-, -C(O)-(CH2)4-, -C(O)-(CH2)5-, -C(O)-(CH2)6--(CH2)2-C(O)-, -(CH2)3-C(O)-, -(CH2)4-C(O)-, -(CH2)5-C(O)-, -(CH2)6-C(O)-, -C(O)-(CH2)2-C(O)-, -CO-(CH2)3-C(O)-, -C(O)-(CH2)4-C(O)-, -C(O)-(CH2)5-C(O)-, -C(O)-(CH2)6-C(O)-, -CH2-C(O)-CH2-, -CH2-C (O)-(CH2)2-,-CH2-C(O)-(CH2)3-,-CH2-C(O)-(CH2)4-,-(CH2)2-C(O)-CH2-,-(CH2)2-C(O)-(CH2)2-,-(CH2)2-C(O)-(CH2)3-,-(CH2)2-C(O)-(CH2)4-,-(CH2)3-C(O)-CH2-,-(CH2)3-C(O)-(CH2)2-,-(CH2)3-C(O)-(CH2)2- )3-、-(CH2)3-C(O)-(CH2)4-、-(CH2)4-C(O)-CH2-、-(CH2)4-C(O)-(CH2)2-、-(CH2)4-C(O)-(CH2)3-、-(CH2)4-C(O-)(CH2)4-、-CH2-O-CH2-、-CH2-O-(CH2)2-、-CH2-O-(CH2)3-、-CH2-O-(CH2)4-、-(CH2)2-O-CH2-、-(CH2)2 -O-(CH2)2-、-(CH2)2-O-(CH2)3-、-(CH2)2-O-(CH2)4-、-(CH2)3-O-CH2-、-(CH2)3-O-(CH2)2-、-(CH2)3-O-(CH2)3-、-(CH2)3-O-(CH2)4-、-(CH2)4-O-CH2-、-(CH2)4-O-(CH2)2-、-(CH2)4-O-(CH2)3-、-(CH2)4-O-(CH2)4-、 More preferably, -(B L ) q - Selected from covalent bonds, -(CH2)5-, -(CH2)8-, -NH-(CH2)5-, -NH-(CH2)8-, -NH-(CH2) 13 -, -NH-(CH2)2-OCH2CH2-, -NH-(CH2)2-(OCH2CH2)2-, -NH-(CH2)2-(OCH2CH2)4-, -NH-( CH2)4-C(O)-NH-(CH2)7-, -NH-(CH2)3-C(O)-NH-(CH2)3-, -NH-(CH2)2-C(O)-NH-CH2-, The compound according to any one of claims 35-39 is selected from the following structures: Use of a compound of Formula IV in the preparation of a medicament for treating diseases or conditions mediated by the simultaneous degradation of estrogen receptor protein and IKZF2 protein, said compound having the following chemical structure: CLM―L―PTM(Form IV); Or its isomers, isotopic derivatives, polymorphs, prodrugs, or pharmaceutically acceptable salts or solvates thereof, wherein: L is a bond that covalently connects the CLM and the PTM, or -(B L ) q -; B L Each occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, S(O), S(O)2, NR L3 S(O)2NR L3 S(O)NR L3 C(O)NR L3 NR L3 C(O)NR L4 NR L3 S(O)2NR L4 C(O), CR L1 =CR L2 C≡C, SiR L1 R L2 P(O)R L1 P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 Cycloalkylene, heterocyclic, aryl, and heteroaryl, wherein the cycloalkylene, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 0-6 R groups. L1 and / or R L2 Group substitution; preferably, B L Each occurrence is independently selected from: CR L1 R L2 O, S, S(O), S(O)2, NR L3 C(O), C≡C, 3-16-membered cycloalkylene, 3-16-membered heterocyclic, 6-10-membered arylene, and 5-10-membered heteroarylene, wherein the 3-16-membered cycloalkylene, 3-16-membered heterocyclic, 6-10-membered arylene, and 5-10-membered heteroarylene are optionally surrounded by 0, 1, 2, or 3 R's. L1 and / or R L2 Group substitution; R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, C. 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, C(O)-C 3-8 Cycloalkyl, C(O)-C 3-11 Heterocyclic groups, OC 6-10 Aryl, O-5-10 heteroaryl, SC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, N(C) 3-8 cycloalkyl)2, N(C) 3-8 cycloalkyl)(C 1-8 Alkyl), N(C) 1-8 Alkylene)(C 3-8 cycloalkyl), NH-C 3-8 Heterocyclic groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8 Heterocyclic group)(C 1-8 Alkyl), NH-C 6-10 Aryl, N(C) 6-10 Aryl)(C 1-8 Alkyl), NH-5-10 heteroaryl, N(5-10 heteroaryl) (C 1-8 Alkyl groups, -OH groups, -NH2 groups, -SH groups, S(O)2P(O) (OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, C(O)-C 1-8 Alkyl, C(O)-OC 1-8 Alkyl, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, S(O)2NH-C 1-8 Alkyl, S(O)2N(C) 1-8 Alkyl)2、S(O)NH-C 1-8 Alkyl, S(O)N(C) 1-8 Alkyl)2、C(O)NH-C 1-8 Alkyl, C(O)NH-C 3-8 cycloalkyl, C(O)NH-C 3-11 Heterocyclic groups, C(O)N(C) 1-8 Alkyl)2, N(C) 1-8 alkyl)C(O)NH(C 1-8 Alkyl), N(C) 1-8 alkyl)C(O)N(C 1-8 Alkyl)2、NHC(O)NH(C 1-8 Alkyl), NHC(O)N(C 1-8 Alkyl)2, NHC(O)NH2, N(C) 1-8 alkyl)S(O)2NH(C 1-8 Alkyl), N(C) 1-8 alkyl)S(O)2N(C 1-8 Alkyl)2, NHS(O)2NH(C 1-8 Alkyl), NHS(O)2N(C 1-8 Alkyl)2 and NHS(O)2NH2, optionally, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic group, C 3-8 Heterocyclic group, C 6-10 The aryl and 5-10 heteroaryl groups are each independently substituted by one or more substituents selected from halogens, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxyl, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl, and haloheteroaryl; preferably, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic group, C 6-10 Aryl and 5-10 heteroaryl groups are each independently selected from F, Cl, Br, I, C. 1-6 The substance is substituted by one or more substituents selected from alkyl, methoxy, and ethoxy groups; q is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; Preferably: B L The definition of q is the same as that in any one of claims 35-40; The definition of CLM is the same as that in any one of claims 35-40; and PTM is a portion of an estrogen receptor protein that binds to it; wherein, the PTM is selected from the following structural formulas: R1 and R2 are each independently selected from N and CR. m ; Each time R3 appears, it is independently selected from H, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano, and amino; wherein the C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C1-C6 alkoxy are optionally replaced by 1, 2, 3, 4, or 5 groups, each independently selected from carboxyl, deuterium, and other groups. Substituents of atoms, halogens, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R3 is... Each occurrence of R4 is independently selected from N and CRm4; Each occurrence of R5 is independently selected from N and CRm5; Each occurrence of R6 is independently selected from N and CRm6; Each occurrence of R7 is independently selected from N and CRm7; R m8 selected from -N(R a )2 and -OR a ; R m9 selected from -C(R a )3, -N(R a )2, -OR a and R a ; or R m8 With R m9 Forming a ring structure; R m8 and R m9 The bonded carbon atoms form saturated or unsaturated C4-C bonds. 10 The subcyclic hydrocarbon group or a 4-10 membered subheterocyclic group containing 1-3 heteroatoms each independently selected from N, O, and S, wherein the saturated or unsaturated C4-C 10 The cyclic hydrocarbon group or 4-10 membered heterocyclic group is unsubstituted or optionally selected from oxo (=O), F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, hydroxy, C1-C6 hydroxyalkyl, cyano, amino, nitro, C3-C8 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 The aryl group is substituted with one or more substituents selected from 5-10 heteroaryl groups; preferably, R m8 and R m9 The carbon atom to which it is attached forms a saturated or unsaturated C5-C7 subcyclic hydrocarbon group or a 5-7 membered subheterocyclic group containing 1-3 heteroatoms, each independently selected from N, O, and S. The saturated or unsaturated C5-C7 subcyclic hydrocarbon group or the 5-7 membered subheterocyclic group is unsubstituted or optionally substituted by one or more substituents selected from oxo (=O), F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, nitro, cyano, oxo, and amino groups; preferably, R m8 and R m9 The carbon atom to which it is attached forms a saturated or unsaturated C5-C7 subcyclic hydrocarbon group or a 5-7 membered subheterocyclic group containing one or two N atoms, wherein the saturated or unsaturated C5-C7 subcyclic hydrocarbon group or the 5-7 membered heterocyclic group is unsubstituted or optionally substituted by one or more substituents selected from oxo (=O), F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, hydroxyl, nitro, cyano and amino; Q is selected independently from CR each time it appears. 11 and N; Q 1 Each occurrence is O, S, or NR. 11 ; Q 2 Each occurrence is either O or CR 11 ; R a R m R m1 R m2 R m3 R m4 R m5 R m6 R m7 R 10 R 11 R p1 R p2 and R p3 Each occurrence is independently selected from H, carboxyl, deuterium, halogen, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, amino, C1-C6 alkylamino, C1-C6 alkylacyl, C1-C6 alkyloxyacyl, and C1-C6 alkylaminoacyl; preferably, R a R m R m1 R m2 R m3 R m4 R m5 R m6 R m7 R 10 R 11 R p1 R p2 and R p3 Each occurrence is independently selected from H, deuterium, F, Cl, Br, I, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkoxy, hydroxyl, C1-C6 hydroxyalkyl, nitro, cyano, and amino; R 12 Each time it appears, it is independently selected from hydroxyl and carboxyl groups; m13, m14, and m15 are each independently selected from 0, 1, 2, 3, 4, and 5; and Each time p appears, it is independently selected from 0, 1, and 2; Indicates a single bond or a double bond; Preferably: B L Each occurrence may be the same or different, and each is independently selected from: CR L1 R L2 O, S, S(O), S(O)2, NR L3 S(O)2NR L3 S(O)NR L3 C(O)NR L3 NR L3 C(O)NR L4 NR L3 S(O)2NR L4 C(O), CR L1 =CR L2 C≡C, SiR L1 R L2 P(O)R L1 P(O)OR L1 NR L3 C(=NCN)NR L4 NR L3 C(=NCN), NR L3 C(=CNO2)NR L4 Cycloalkylene, heterocyclic, aryl, and heteroaryl, wherein the cycloalkylene, heterocyclic, aryl, and heteroaryl groups are optionally surrounded by 0-6 R groups. L1 and / or R L2 Group substitution; R L1 R L2 R L3 and R L4 Each time it appears, it is independently selected from H, halogen, C. 1-8 Alkyl, OC 1-8 Alkyl, SC 1-8 Alkyl, NH-C 1-8 Alkyl, N(C) 1-8 Alkyl)2, C 3-11 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 3-11 Heterocyclic groups, OC 3-8 cycloalkyl, OC 3-11 Heterocyclic groups, OC 6-10 Aryl, O-5-10 heteroaryl, SC 3-8 cycloalkyl, NH-C 3-8 cycloalkyl, N(C) 3-8 cycloalkyl)2, N(C) 3-8 cycloalkyl)(C 1-8 Alkyl), NH-C 3-8 Heterocyclic groups, N(C) 3-8 Heterocyclic group)2, N(C 3-8 Heterocyclic group)(C 1-8 Alkyl), NH-C 6-10 Aryl, N(C) 6-10 Aryl)(C 1-8 Alkyl), NH-5-10 heteroaryl, N(heteroaryl) (C 1-8 Alkyl groups, -OH, -NH2, -SH, SO2P(O)(OC) 1-8 Alkyl)(C 1-8 Alkyl), P(O)(OC 1-8 Alkyl)2、C≡CC 1-8 Alkyl, C≡CH, CH=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl)=CH-(C 1-8 Alkyl), C(C) 1-8 Alkyl) = C(C 1-8 Alkyl)2, Si(OH)3, Si(C 1-8 Alkyl)3, Si(OH)(C 1-8 Alkyl)2, C(O)-C 1-8 Alkyl, -C(O)2H, -CN, -CF3, -CHF2, -CH2F, -NO2, -SF5, S(O)2NH-C 1-8 Alkyl, S(O)2N(C) 1-8 Alkyl)2、S(O)NH-C 1-8 Alkyl, S(O)N(C) 1-8 Alkyl)2、C(O)NH-C 1-8 Alkyl, C(O)N(C) 1-8 Alkyl)2, N(C) 1-8 alkyl)C(O)NH(C 1-8 Alkyl), N(C) 1-8 alkyl)C(O)N(C 1-8 Alkyl)2、NHC(O)NH(C 1-8 Alkyl), NHC(O)N(C 1-8 Alkyl)2, NHC(O)NH2, N(C) 1-8 alkyl)S(O)2NH(C 1-8 Alkyl), N(C) 1-8 alkyl)S(O)2N(C 1-8 Alkyl)2, NHS(O)2NH(C 1-8 Alkyl), NHS(O)2N(C 1-8 Alkyl)2, and NHS(O)2NH2, optionally, the C 1-8 Alkyl, C 3-11 cycloalkyl, C 3-8 cycloalkyl, C 3-11 Heterocyclic group, C 3-8 Heterocyclic group, C 6-10 The aryl and 5-10 heteroaryl groups are each independently substituted by one or more substituents selected from halogen, alkyl, heteroalkyl, alkenyl, alkoxy, hydroxyl, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycloyl, halocycloalkyl, haloheteroalkyl, alkylamino, aryl, heteroaryl, haloaryl and haloheteroaryl; q is an integer greater than or equal to 1; preferably 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20; The definition of CLM is the same as that in any one of claims 27-32; and PTM is the portion of the estrogen receptor protein that binds. The use as described in claim 41, wherein, The PTM is selected from: The use as described in any one of claims 41-42, wherein, The compound is selected from: A pharmaceutical composition comprising a compound of any one of claims 35-40 and a pharmaceutically acceptable excipient. A method for degrading IKZF2 protein in a subject or biological sample, comprising administering a compound of any one of claims 35-40 to a subject or contacting a biological sample with a compound of any one of claims 35-40. Use of the compound according to any one of claims 35-40 or the pharmaceutical composition according to claim 44 in the preparation of a medicament for degrading IKZF2 protein in a subject or biological sample. The compound according to any one of claims 35-40 or the pharmaceutical composition according to claim 44, for degrading IKZF2 protein in a subject or biological sample. A method for treating a disease or condition in a subject of need by simultaneously degrading estrogen receptor protein and IKZF2 protein, or for treating or preventing a disease or condition mediated by estrogen receptor protein and IKZF2 in a subject of need, comprising administering to the subject the compound as described in claims 41-43. A compound as described in claims 41-43, used to treat or prevent a disease or condition in a subject of need by simultaneously degrading estrogen receptor protein and IKZF2 protein, or to treat or prevent a disease or condition mediated by estrogen receptor protein and IKZF2 in a subject of need. The method, use, compound, or pharmaceutical composition as described in any one of claims 41-43 or 44-49, wherein the disease is cancer, preferably breast cancer, ductal carcinoma of the breast, prostate cancer, mantle cell lymphoma, chronic myeloid leukemia, acute myeloid leukemia, myeloid monocytic leukemia, non-small cell lung cancer, lung adenocarcinoma, or cervical cancer.

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